Association of Piebaldism with
Café-au-Lait Macules
Kansal and Agarwal

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Finacea® (azelaic acid) Foam, 15% is indicated for topical treatment of
the inflammatory papules and pustules of mild to moderate rosacea.

The first and only prescription foam approved by the FDA for the treatment of rosacea
In the art of rosacea therapy...

Proven efficacy has
another profile
with Finacea Foam
®

IMPORTANT SAFETY INFORMATION
Warnings and Precautions
Skin Reactions: There have been isolated reports of hypopigmentation
after use of azelaic acid. Because azelaic acid has not been well studied
in patients with dark complexion, monitor these patients for early signs of
hypopigmentation.
Eye and Mucous Membranes Irritation: Azelaic acid has been reported to
cause irritation of the eyes. Avoid contact with the eyes, mouth and other
mucous membranes. If Finacea® Foam does come in contact with the
eyes, wash the eyes with large amounts of water and consult a healthcare
professional if eye irritation persists.
Flammability: The propellant in Finacea® Foam is flammable. Instruct the
patient to avoid fire, flame, and smoking during and immediately following
application. Do not puncture and/or incinerate the containers. Do not expose
containers to heat and/or store at temperatures above 120°F (49°C).
Most Common Adverse Reactions
In clinical studies, the most frequently observed adverse reactions in ≥ 0.5%
of subjects treated with Finacea® Foam included local site pain (6.2%),
pruritus (2.5%), dryness (0.7%), and erythema (0.7%).
For Topical Use Only
Finacea® Foam is not for oral, ophthalmic or intravaginal use.
Avoid the use of occlusive dressings or wrappings at the application site.
Avoid use of alcoholic cleansers, tinctures and astringents, abrasives and
peeling agents.
Patients should be reassessed if no improvement is observed upon
completing 12 weeks of therapy.
You are encouraged to report negative side effects of prescription drugs
to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.
For important risk and use information, see the full Prescribing Information
at www.finaceafoam.com.
For important risk and use information, see the Brief Summary on the
following page.

For Topical Use Onlyâ&#x20AC;&#x201C;Not for Oral, Ophthalmic or Intravaginal Use
Rx only
BRIEF SUMMARY
CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
Finacea (azelaic acid) Foam, 15% is indicated for topical treatment of the
inflammatory papules and pustules of mild to moderate rosacea.
5
WARNINGS AND PRECAUTIONS
5.1
Skin Reactions
There have been isolated reports of hypopigmentation after use of azelaic
acid. Because azelaic acid has not been well studied in patients with dark
complexion, monitor these patients for early signs of hypopigmentation.
5.2
Eye and Mucous Membranes Irritation
Azelaic acid has been reported to cause irritation of the eyes. Avoid contact
with the eyes, mouth and other mucous membranes. If Finacea Foam does
come in contact with the eyes, wash the eyes with large amounts of water
and consult a physician if eye irritation persists.
5.3
Flammability
The propellant in Finacea Foam is flammable. Instruct the patient to avoid
fire, flame, and smoking during and immediately following application. Do
not puncture and/or incinerate the containers. Do not expose containers to
heat and/or store at temperatures above 120Â°F (49Â°C).
6
ADVERSE REACTIONS
The following adverse reactions are described elsewhere in the prescribing
information:
t )ZQPQJHNFOUBUJPO[see Warnings and Precautions (5.1)].
t Eye and Mucous Membranes Irritation [see Warnings and Precautions
(5.2)].
6.1
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions,
adverse reaction rates observed in the clinical trials of a drug cannot be
directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
Finacea Foam was evaluated for the treatment of papulopustular rosacea
in two multicenter, randomized, double-blind, vehicle-controlled, 12-week
clinical trials involving a total of 1362 (Finacea Foam, 15%: 681; vehicle:
681) subjects. Overall, 95.7% of subjects were White, 73.4% were female,
and the mean age was 50.6 years.
Table 1: Adverse Reactions Occurring in â&#x2030;Ľ 0.5% of Subjects Treated with
Finacea Foam Compared with Subjects Treated with Vehicle
System/Organ Class
Preferred

Finacea Foam,
15% (N=681)
n (%)

Vehicle
(N=681)
n (%)

General disorders and application site conditions
Application site pain*
Application site pruritus
Application site dryness
Application site erythema

42 (6.2%)
17 (2.5%)
5 (0.7%)
5 (0.7%)

10 (1.5%)
2 (0.3%)
5 (0.7%)
6 (0.9%)

* â&#x20AC;&#x153;Application site painâ&#x20AC;? is a term used to describe disagreeable skin
sensations, including burning, stinging, paraesthesia and tenderness.
6.2
Post-Marketing Experience
)ZQFSTFOTJUJWJUZ
SBTIBOEXPSTFOJOHPGBTUINBIBWFCFFOSFQPSUFEGSPN
the postmarketing experience of azelaic acid-containing formulations.
Because these reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their frequency
or establish a causal relationship to drug exposure.
Local Tolerability Studies
In a 21-day cumulative irritation study under occlusive conditions, mildto-moderate irritation was observed for azelaic acid pre-foam emulsion. In
BIVNBOSFQFBUJOTVMUQBUDIUFTU )3*15
TUVEZ
OPTFOTJUJ[BUJPOQPUFOUJBM
was observed for azelaic acid pre-foam emulsion.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Teratogenic Effects: Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women.
Therefore, Finacea Foam should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.

Dermal embryofetal developmental toxicology studies have not been
performed with azelaic acid, 15% foam. Oral embryofetal developmental
studies were conducted with azelaic acid in rats, rabbits, and cynomolgus
monkeys. Azelaic acid was administered during the period of organogenesis
in all three animal species. Embryotoxicity was observed in rats, rabbits,
and monkeys at oral doses of azelaic acid that generated some maternal
toxicity. Embryotoxicity was observed in rats given 2500 mg/kg/day [162
UJNFTUIFNBYJNVNSFDPNNFOEFEIVNBOEPTF .3)%
CBTFEPOCPEZ
surface area (BSA)], rabbits given 150 or 500 mg/kg/day (19 or 65 times
UIF.3)%CBTFEPO#4"
BOEDZOPNPMHVTNPOLFZTHJWFONHLHEBZ
UJNFT UIF .3)% CBTFE PO #4"
B[FMBJD BDJE /P UFSBUPHFOJD FGGFDUT
were observed in the oral embryofetal developmental studies conducted in
rats, rabbits and cynomolgus monkeys.
An oral peri- and post-natal developmental study was conducted in rats.
Azelaic acid was administered from gestational day 15 through day 21
postpartum up to a dose level of 2500 mg/kg/day. Embryotoxicity was
PCTFSWFEJOSBUTBUBOPSBMEPTFPGNHLHEBZ UJNFTUIF.3)%
based on BSA) that generated some maternal toxicity. In addition, slight
disturbances in the post-natal development of fetuses was noted in rats
at oral doses that generated some maternal toxicity (500 and 2500 mg/
LHEBZBOEUJNFTUIF.3)%CBTFEPO#4"
/PFGGFDUTPOTFYVBM
maturation of the fetuses were noted in this study.
8.3
Nursing Mothers
It is not known if azelaic acid is secreted into human milk in vivo/PXFMM
controlled studies of topically administered azelaic acid in nursing women
BSF BWBJMBCMF /FWFSUIFMFTT
UIF EFDJTJPO UP EJTDPOUJOVF OVSTJOH PS UP
discontinue the drug should take into account the importance of the drug
to the mother.
8.4
Pediatric Use
The safety and efficacy of Finacea Foam in children below the age of 18
years have not been established.
8.5
Geriatric Use
Of the total number of subjects in clinical studies of Finacea Foam, 18.8
QFSDFOUXFSFBOEPWFS
XIJMFQFSDFOUXFSFBOEPWFS/PPWFSBMM
differences in safety or effectiveness were observed between these subjects
and younger subjects, and other reported clinical experience has not
identified differences in responses between the elderly and younger patients,
but greater sensitivity of some older individuals cannot be ruled out.
17
PATIENT COUNSELING INFORMATION
Inform patients using Finacea Foam of the following information and
instructions:
t 'PSFYUFSOBMVTFPOMZ
t $MFBOTFBGGFDUFEBSFB T
XJUIBWFSZNJMETPBQPSBTPBQMFTTDMFBOTJOH
lotion and pat dry with a soft towel.
t 4IBLFXFMMCFGPSFVTF
t "WPJEVTFPGBMDPIPMJDDMFBOTFST
UJODUVSFTBOEBTUSJOHFOUT
BCSBTJWFTBOE
peeling agents.
t "WPJE DPOUBDU XJUI UIF FZFT
NPVUI BOE PUIFS NVDPVT NFNCSBOFT *G
Finacea Foam does come in contact with the eyes, wash the eyes with
large amounts of water and consult your physician if eye irritation
persists.
t *GBMMFSHJDSFBDUJPOTPDDVS
EJTDPOUJOVFVTFBOEDPOTVMUZPVSQIZTJDJBO
t 8BTIIBOETJNNFEJBUFMZGPMMPXJOHBQQMJDBUJPOPG'JOBDFB'PBN
t $PTNFUJDTNBZCFBQQMJFEBGUFSUIFBQQMJDBUJPOPG'JOBDFB'PBNIBTESJFE
t "WPJEUIFVTFPGPDDMVTJWFESFTTJOHTBOEXSBQQJOHT
t 5PIFMQNBOBHFSPTBDFB
BWPJEBOZUSJHHFSTUIBUNBZQSPWPLFFSZUIFNB
flushing, and blushing. These triggers can include spicy and thermally hot
food and drinks such as hot coffee, tea, or alcoholic beverages.
t 5IF QSPQFMMBOU JO 'JOBDFB 'PBN JT nBNNBCMF "WPJE mSF
nBNF
PS
smoking during and immediately following application.
t %JTDBSEQSPEVDUXFFLTBGUFSPQFOJOH
ÂŠ
#BZFS)FBMUI$BSF1IBSNBDFVUJDBMT*OD"MMSJHIUTSFTFSWFE
Manufactured for:

Authors interested in submitting a paper should refer to the instructions
located online at: http://www.skinmedjournal.com/author-info.html.
Submissions should be e-mailed to the Editor at: larryderm@yahoo.com

Publishing
PUBLISHER
Art Kalaka

Disclaimer: The Publisher, Editors, and Editorial Board cannot be held
responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed herein
do not necessarily reflect those of the Publisher, Editors, and Editorial
Board, neither does the publication of advertisements constitute any endorsement by the Publisher, Editors, and Editorial Board of the products
or services advertised. The Publisher, Editors, Editorial Board, Reviewers,
Authors, and Affiliated Agents shall not be held responsible or in any way
liable for the continued accuracy of the information or for any errors,
inaccuracies, or omissions of any kind in this publication, whether arising
from negligence or otherwise, or for any consequences arising thereafter.

n an era of open access publishing and pressure for physicians, residents, and medical students to publish an excessive
amount of papers, the phenomenon of predatory open access
journals has become increasingly prevalent. The term “predatory
publishers” was coined by Jeffrey Beall to describe how journals
and publishers take advantage of open access publishing for their
own profit. Jeffrey Beall is an academic and research librarian at
Auraria Library of the University of Colorado, Denver. He describes how predatory publishers aggressively and often dishonestly advertise to unsuspecting authors and invite submissions to
questionable journals, often charging the authors a large fee for
publication in a journal that may not be peer-reviewed.

and content licenses.1,2 (It is true that medical publishers in the
19th century often charged authors for publishing in journals
or in books, which morphed into the vanity press of the 20th
century.) The potential to increase revenue by recruiting authors
has led to these pop-up journals that exist only for the collection of fees.1,3 Some fraudulent journals also exist, because some
commercial and professional societies create journals to increase
their journal portfolios. These journals generally work by spamming the e-mails of clinicians, researchers, and academic faculty
with the “opportunity” to publish in a new journal, to serve as
a reviewer or editor of a new journal, or to speak at “renowned”
conferences.1,3

Not only does this hurt unknowing authors who are trying to
publish their work, but it also provides a route for the publication of low-quality and inaccurate work. Its inclusion as legitimate information dilutes the wealth of scientific knowledge used
to educate physicians, researchers, and the general public. It is
important to raise awareness and educate. Unsuspecting authors
should be made aware of this unfortunate phenomenon, as it not
only harms the integrity of the peer-review process and scientific
research but also has the potential to harm patients.

These journals are often deceptive about their legitimacy. Contributions are often not peer-reviewed, and the reviewers and
journal editor often have no credentials.1,2 Some try to lure authors by giving the journal a name similar to those of reputable
journals and a logo reminiscent of a reputable journal’s.1 After
authors sign away the copyright, they may be asked to pay unexpected fees that can reach as high as $1,800,1,2,4 only to find
their published papers inaccessible through established search
mechanisms.2

BACKGROUND

Little empirical research has been done on predatory publishing.2
Beall recognized as a leading expert in the field, estimates that it
accounts for 5% to 10% of author-pays.5 One assessment found
that predatory journals published 400,000 papers in 2014, at
an average cost to the author of $178 per paper.6 In 2015, the
Federal Trade Commission set an example with its first lawsuit
against the academic journal publishers OMICS Group and two
of its subsidiaries, announcing that the publisher was deceiving
scholars and misrepresenting the editorial rigor of its journals.4

Journals offer a range of traditional and open access options for
authors. In the open access model, authors pay contributionprocessing charges for immediate availability to the public on the
Internet.1,2 There are also options to pay fees for various levels of
delayed public access for specific types of papers.1
Before the era of online access, journal owners and publishers
relied not on fees from authors, but on journal subscriptions

Although the prevalence of these fraudulent journals is alarming, we should keep in mind that they represent a tiny minority
of open access journals. Most open access journals do, indeed,
follow the standard practices and standards of scholarly work.3
Because a journal is for profit does not necessarily mean that the
quality or integrity of the work is any less, as many reputable
open access journals use contribution-processing charges to cover costs.3 Unfortunately, the predatory publishers and journals
give bad publicity to the open access paradigm, which has provided many benefits in terms of making scientific data available
to as many readers as possible.

prey to these journals. Hopefully, this is due, in large part, to a
lack of awareness of these journals, highlighting the importance
of educating the medical community, in particular, about this
problem. The fact that nonpeer-reviewed research and information is being added to the body of knowledge that we, as scientists, rely on is dangerous in the field of medicine. We should not
use predatory journals, and many experts have even proposed
they be excluded from databases.9,10
References

Because the integrity of journals falls on a spectrum,5,7 Beall has
devised useful criteria for choosing legitimate journals. He suggests that the direct contact information for the editor should be
provided and that the names and roles of the review panel and
editorial board should be clearly delineated. The journal should
show an impact factor, and the name of the journal should not
sound similar to the name of another journal. He also cautions
to be wary of e-mail invitations, to read the journal, and to contact previous authors. Additionally, the editorial board should
include experts in the field with full affiliations.1,3,4,8
There is a fine line between low-quality and predatory publishers, so the Directory of Open Access Journals has created lists
of vetted journals rather than a list of blacklisted journals. In
essence, to make the list, the journal must be scholarly, make the
content immediately available, have a peer-review process, and
provide a registered International Standard Serial Number.3,7
Some argue that additions to this process will not be fast enough
to keep up with the surge of new journals and publishers and
that a blacklist, like Beall’s, is better, because it would be able to
keep pace.4 Beall updated his lists continually for viewing, until
January 15, 2017, when they abruptly went dark.
CONCLUSIONS
The recent success of predatory publishers has been due to a
combination of authors wanting a large number of publications
on their resumes, and the fact that, in the open access era of
publishing, for-profit journals and publishers compete with each
other for writers. Although it is questionable ethics, the motive for the creation of fraudulent journals is obvious—to make

ajdel et al, in an outstanding paper in this issue of
SKINmed, report a remarkable case of a patient with a
blue (due to cobalt) tattoo who experienced a severe systemic reaction after attempting removal of the tattoo with a 50%
trichloroacetic acid tattoo removal solution.1 This was despite
having neither atopy nor dermatitis as a predisposing factor. The
reaction only abated after surgical excision of the tattoo with its
cobalt-based pigment. This appears to be the first such reaction
due to cobalt ever reported, but even if someone finds another
one, it is rare and certainly unusual.
The patient is no doubt grateful for having been cured, but may
sensibly ask “why me?” It is a reasonable question deserving of
the attention of all of us.
HISTORICAL BACKGROUND
In 1900, Paul Ehrlich (1854–1915) proposed what is probably
the first modern mechanism to account for antigen recognition
and antibody formation. In his “side-chain hypothesis,” Ehrlich
proposed that some unnamed cells have side chains, which react
with a foreign antigen against which they then produce antibody.
In 1955, Niels Kaj Jerne (1911–1994), who won the Nobel Prize
in Physiology or Medicine in 1984, noted that the human body
contains a vast array of “background” antibody before de novo
antigen exposure, which might be expected to react with virtually any antigen encountered.1–5

Lederberg (1925–2008), who showed experimentally that one
B lymphocyte only produces antibody with a single antigenic
specificity.6
In 1957 and again in a book published in 1959, Sir Frank Macfarlane Burnet (1899–1985) published his “clonal selection
theory of acquired immunity.” In this, one or more mechanisms were proposed to expose an array of immunocompetent
cells to foreign antigens, allowing the clones that produced antibody reacting with that antigen to be stimulated to divide;
this would lead in a logarithmic fashion to additional cells
synthesizing that reactive antibody. As the process progressed,
only those clones that produced the antibody with the higher
affinities would continue to be stimulated, so that the affinity
of the antibody would increase as the process continued, an observation observed clinically and experimentally and that had
to be explained by the theory.1 This system, which is duplicated
in the B-cell and T-cell systems, acts in concert with similar
systems, including particularly the more germline-based “innate” immune system.7

THE ANTIBODY-PRODUCING CELL

This provides us with an explanation of how the basic immune
system works, but to the discerning eye it raises more questions
than it answers. Interestingly, this is as far as the account on
Wikipedia takes us; apparently, the authors considered all the
important questions to be addressed by the above. To the contrary, this is just where things get interesting, and where the field
becomes most relevant to dermatologists.

In 1957, David W. Talmage (1919–2014) proposed that every
antibody-producing cell produces only one unique sort of antibody (ie, antibody with one antigen-binding site). This concept
was refined in 1958 by Gustave Nossal (b. 1931) and Joshua

The antibody diversity that characterizes the acquired immunity
with which we address and cope with the vast majority of environmental antigens is not accounted for by genes for the variable
binding sites of antibody. These are not present in the germline;

they must be generated by mutations that arise in the precursors of our antibody-producing clones of cells that are selected
to proliferate upon antigen exposure as per the clonal selection
model.
STIMULATING LYMPHOCYTES
But herein lies a problem. One should expect that this population would be a heterogeneous group, with some cells showing
multiple mutations, and thus possessing excellent antibody diversity, but far, far more cells showing far fewer mutations and
poor antibody diversity. For this system to work, there must be
a powerful mechanism that begins by stimulating the target cells
to replicate, and then, over time, selectively favors those which
have undergone multiple mutations, while slowly but surely
eliminating those that have undergone only a few mutations.
This is achieved by strongly stimulating lymphocytes in development with major transplantation “HLA” antigens (in humans),
which then slowly grow more toxic to cells that have undergone
too few mutations in their antibody-binding sites.

Modern societies protect their children, who subsequently do
not become exposed to many antigens during development.
This has many benefits, such as reduced infections, but may also
contribute to unusual reactions, such as that experienced by this
patient. It may also contribute to the high incidence of skin diseases such as atopy and dermatitis experienced by members of
our society, not to mention autoimmune diseases, some of which
are quite serious.
CONCLUSIONS
More attention needs to be paid to examining the incidence of
such diseases in developed, “first-world” environments versus
less developed areas, where protecting children from such “hazards” is less rigorous.
References

There are good and bad things about the resulting diverse pool
of potential reactive lymphocytes. A major benefit is that a very
wide range of antibody is created. A major flaw is that it is sometimes not quite wide enough. The histocompatibility antigens
that stimulate the lymphocytes can only stimulate so many
clones; in most cases, some that would otherwise be possible are
simply not stimulated by this particular set of major histocompatibility antigens. The result is that certain major histocompatibility antigens are linked to certain autoimmune diseases, and
there is considerable variability in the ability of different individual people to respond to certain antigens.8,9
ANTIGENIC EXPOSURE
Even this, however, does not completely explain why our erstwhile patient suffered her reaction to cobalt. The patient’s antigenic exposure experience may have also played a role. There are
a number of interesting inbred animal models in which a high
proportion of the animals develop a severe autoimmune disease
unless they receive a strong antigen exposure, such as a nematode
infection, at an early age; this, after treatment and elimination
of the source of antigen, prevents the autoimmune disease from
developing.10

Telangiectasia Macularis Eruptiva
Perstans: Report of Three Cases
Gizem Tumer, MD; Tiffany Jow, BS;2 Sean McElligott, MD;
Robert A. Schwartz, MD, MPH;2 W. Clark Lambert MD, PhD2
Abstract
Telangiectasia macularis eruptiva perstans (TMEP) is a rare, heterogeneous disease of mast cell proliferation. The variable clinical presentation of TMEP, coupled with its rarity, makes the recognition and diagnosis of this disease difficult and challenging for clinicians. The
histopathologic findings with hematoxylin and eosin staining that distinguish TMEP from a normal skin biopsy can be so subtle that
confirmation of the diagnosis with additional special stains (c-Kit, Giemsa, toluidine blue) is strongly recommended. We describe three
cases that highlight the variable clinical presentation of TMEP. One patient experienced only a localized skin manifestation, another an
aggressive clinical course with systemic involvement, and a third diffuse skin involvement with mild fatigue, muscle pain, and weight gain.
(SKINmed. 2017;15:171–174)

T

MEP represents a rare clinical form of cutaneous mastocytosis that is most commonly seen in adults, but
also rarely in children. Conventionally, TMEP has been
thought to be limited to the skin, but systemic manifestations
have been documented. Reports have also demonstrated associations between TMEP and myelodysplasia, myeloproliferative
disorders, acute myeloid leukemia, and/or lymphoproliferative
disease—an association that has not gained much recognition
among hematologists.1 We describe three varied and atypical
cases of TMEP. In doing so, we aim to further contribute to the
literature on the classification of this rare but fascinating disease.
CASE 1
A 73-year-old woman presented with hyperpigmented patches
on her thighs, knees, ankles, and dorsum of the feet. Laboratory tests and physical examination did not reveal any systemic
involvement. A skin biopsy was performed, and histological examination demonstrated dilated vessels and associated perivascular mast cells, indicative of TMEP (Figure 1). Metachromasia
of the mast cells’ cytoplasmic granules was revealed on toluidine
blue staining, which highlighted an increased number mast cells
around the superficial vessels in the papillary dermis (Figure
1). Some mast cells in the superficial region of the dermis also
showed c-Kit immunoreactivity, further confirming the diagno-

sis of TMEP. After 4 years, she was still asymptomatic, and no
further studies had been performed.
CASE 2
A 28-year-old woman presented to a doctor’s office with a 3-day
history of oral labial edema with burning and pruritus. She had
taken Benadryl® at home and had also received a Benadryl® injection, albeit without relief. Initially, she presented with lesions on
her forehead, which eventually spread to involve the remainder
of her body and continued to persist from 5 minutes to several
hours. Systemic involvement was noted as she also experienced
flushing, dizziness, tinnitus, dyspnea, wheezing, cough, arthralgia, and daily abdominal cramps with diarrhea. A referral was
made for further evaluation from a bone marrow biopsy, and
the report came back negative for bone marrow involvement.
A diagnosis of TMEP was suspected, and confirmation was attained through laboratory examination demonstrating positive
toluidine blue and Giemsa stains as well as positive c-Kit immunoreactivity (Figure 2).
CASE 3
A 36-year-old woman was seen with an eruption that had been
present for more than a year. It had initially started on her face

and subsequently spread to her chest, the upper regions of her
arms, and her hands. Her description of the eruption was that it
was focally pruritic and painful. She also complained of systemic
features such as fatigue, muscle pain in the shoulders, and weight
gain. Physical examination demonstrated diffuse scattered telangiectasias of the face, upper part of the palate, buccal-labial mucosa, neck, upper areas of the chest and arms, palms, and fingers.

A skin biopsy was performed, and histological examination revealed dilated blood vessels and an increased number of mast
cells in the superficial part of the dermis (Figure 3). To confirm
the diagnosis of TMEP, laboratory examination with toluidine
blue and Giemsa stains was performed (Figure 4). This revealed
perivascular mast cells, which then were found to be positive for
CD117 (c-Kit) on immunostaining (Figure 4).

DISCUSSION
Cutaneous mastocytosis is a mast cell proliferative disorder with
at least four different clinical forms: urticaria pigmentosa, solitary mastocytoma, diffuse cutaneous mastocytosis, and TMEP.1–
3
Clinically, TMEP presents as patchy erythematous lesions
consisting of reddish-brown macules with telangiectasias and
hyperpigmentation. These lesions typically range between a few
millimeters and several centimeters in diameter. They tend to be
SKINmed. 2017;15:171–174

located symmetrically over the trunk and extremities, and rarely
occur on the face.1,2,4,5
Accurate diagnosis of TMEP can be difficult as Darier sign (urtication on rubbing) is often minimal or absent, contrasting
with other forms of mastocytosis. This is because the lesions
are characteristically paucicellular, and the few mast cells may
not yield significant degranulation to exhibit dermographism
and the characteristic Darier sign seen in most mastocytoses.2,5,6

173

Telangiectasia Macularis Eruptiva Perstans

May/June 2017

ORIGINAL CONTRIBUTION

Occasionally, urticaria pigmentosa coexists with this lesion, but
TMEP may be distinguished from urticaria pigmentosa by the
presence of overlying telangiectases in TMEP.
Systemic involvement may be present and is the result of mast
cell degranulation with subsequent release of multiple mediators.
Features of systemic involvement in TMEP include flushing, blistering, pruritus, cardiac arrhythmias, dyspnea, asthma exacerbations, hypotension, gastrointestinal upset, acid reflux, peptic ulcer
disease, diarrhea, splenomegaly, increased numbers of mast cells in
the bone marrow, abnormal skeletal radiographs, irritability, and
nonspecific neuropsychiatric clinical manifestations.1,3,5,6
Histologically, TMEP is characterized by subtly increased
numbers of ovoid to spindle-shaped mast cells that have a tendency to infiltrate the papillary dermis and surrounding dilated
superficial capillaries and venule.3,7 Giemsa and toluidine blue
stains may then be used to help distinguish mast cells from
histiocytes. Tissue sections showing more than 5 to 10 mast
cells are confirmatory for the diagnosis. In addition, a c-Kit
(CD117) immunohistochemistry assay can be used to further
confirm the diagnosis, as c-Kit is a proto-oncogene that codes
for a tyrosine kinase receptor (CD117) present on mast cells
and melanocytes.7

plus UVA therapy is often reserved for severe cases of TMEP and
treats the pruritus by suppressing the histamine release.7 Intralesional triamcinolone or potent topical steroids may also be used
to cutaneous lesions, but recurrence is frequent and this treatment seems to work only temporarily.8 In addition, skin atrophy,
striae, and risk of systemic absorption tend to limit the use of
corticosteroids.9
Conclusions
The cases presented here illustrate the diverse presentations of
systemic manifestations of mastocytosis that may accompany
TMEP. Whereas no systemic features were noted in case 1, significant systemic involvement was demonstrated in cases 2 and
3; furthermore, in case 3, lesions started on the face, an unusual
location for TMEP. These various presentations of TMEP emphasize the difficulty, albeit importance, of recognizing this
disease, as appropriate workup is mandatory to determine the
proper course of treatment in any cases that present with suspicion for TMEP.
References
1 Briley LD, Phillips CM. Cutaneous mastocytosis: a review
focusing on the pediatric population. Clin Pediatr (Phila).
2008;47:757–761.

Once suspected from the clinical presentation, the diagnosis
should be confirmed by a skin biopsy and further diagnostic
tests. Caution should be taken during the skin biopsy to use
lidocaine without epinephrine, and to inject around the biopsy
site, not directly into it, as direct trauma and epinephrine can
stimulate mast cell degradation.8 For adults with cutaneous mastocytosis, it is recommended that a skin biopsy, complete blood
count with differential, and bone marrow biopsy be performed
to exclude the presence of an associated hematologic condition.
If systemic involvement is suspected, further evaluation is needed depending on the patient’s clinical manifestations.3,8

As TMEP is a rare condition; a definitive treatment has yet to
be documented. However, individual cases have reported good
responses to psoralen plus UVA therapy, 585 nm flash lamppumped dye laser, antihistamines, cromolyn sodium, topical and
oral corticosteroids, leukotriene antagonists, and some chemotherapeutic agents such as interferon-α2b and cladribine.3,4,6,7
Treatment depends on the presence or absence of systemic involvement, which further emphasizes the importance of accurate
initial diagnosis.

Evaluation of Autoimmune Bullous
Diseases in Elderly Patients in Iran:
A 10-Year Retrospective Study
Maryam Ghiasi, MD; Maryam Daneshpazhooh, MD;
Muhammadkhuja Ismonov, MD; Cheyda Chams-Davatchi, MD
Abstract
Autoimmune bullous diseases (ABDs) are uncommon but significant skin disorders with relatively high morbidity and mortality. Some
surveys have been carried out to describe the spectrum of ABDs in a region, but this is the first that has focused on ABDs in elderly patients. This study was conducted to determine the clinicoepidemiologic features of ABDs in elderly patients. Medical records of all ABD
patients with disease onset after the age of 60 years who presented to the Autoimmune Bullous Diseases Research Center, Tehran, Iran
between April 2003 and March 2013 were reviewed. Patients with dermatitis herpetiformis were not included. During the 10-year period
studied, 296 patients with ABD and disease onset after 60 years of age were diagnosed. Bullous pemphigoid (BP) was observed to be the
most common ABD (48.3%), followed by pemphigus vulgaris (45.3%), pemphigus foliaceus (3.7%), mucous membrane pemphigoid
(1.4%), paraneoplastic pemphigus (0.7%), epidermolysis bullosa acquisita (0.3%), and linear IgA bullous disease (0.3%). A predominance
in women was observed for total ABDs, BP, and pemphigus vulgaris. Although Iran is known to have a high prevalence of pemphigus, BP
is the most frequent ABD among elderly patients in Iran, highlighting the importance of the clinical diagnosis of BP in elderly patients.
(SKINmed. 2017;15:175–180)

A

utoimmune bullous diseases (ABDs) are acquired disorders characterized by overlapping features with involvement of the skin and mucous membranes, and significant morbidity and mortality. The main pathogenic factors
in these disorders are autoantibodies against desmosomal and
hemidesmosomal structural proteins in the skin. In the pemphigus group, intraepidermal loss of cell adhesion occurs due
to autoantibodies against desmosomal proteins. This group includes pemphigus vulgaris (PV), pemphigus foliaceus (PF), IgA
pemphigus, and paraneoplastic pemphigus. Pemphigus vegetans
is considered a variant of PV, and pemphigus erythematosus a
variant of PF. In subepidermal ABDs, autoantibodies against
structural proteins of the dermoepidermal junction result in bulla formation at the level of the dermoepidermal junction. This
group includes bullous pemphigoid (BP), mucous membrane
pemphigoid, pemphigoid gestationis, epidermolysis bullosa acquisita, and linear IgA bullous disease.1
ABDs occur in all ages, and their incidence varies greatly in different regions of the world. Many published epidemiologic stud-

ies have focused on pemphigus, but few have encompassed the
total spectrum of ABDs. Few surveys have been carried out to
determine the entire spectrum of ABDs in Iran.2,3 Pemphigus is
known to be especially common in Iran.4–7 To the best of our
knowledge, this is the first study to evaluate ABDs in elderly
patients; it was conducted to determine the subtypes of ABDs in
elderly patients in Iran over a 10-year period. We also collected
data on the clinical manifestations, interval between onset of disease and diagnosis, and methods of treatment in our patients.
METHODS
This retrospective, cross-sectional study was carried out in the
Autoimmune Bullous Diseases Research Center (ABDRC) at
Razi Hospital, Tehran, Iran. ABDRC at Razi Hospital is the major tertiary referral center caring for patients with ABDs. The
medical records of all newly diagnosed patients presenting to
the ABDRC between April 2003 and March 2013 were examined. Patients with an onset of the disease after 60 years of age
were included in the study. The diagnoses in all patients were

suspected clinically and confirmed by histopathology and direct
immunofluorescence. Enzyme-linked immunosorbent assay for
the detection of anti-desmoglein 1 and 3 antibodies in serum
and indirect immunofluorescence were performed in some of
the patients. Direct immunofluorescence on salt-split skin was
performed to confirm epidermolysis bullosa acquisita. Patients
with dermatitis herpetiformis were not included in our study because they are seen and managed in general dermatology clinics.
RESULTS
A total of 296 patients, 60 years old or older, were diagnosed
with ABD and a disease onset during the study period. There
were 168 (56.8%) women and 128 (43.2%) men. The most
common disease was BP, and the second most common, with
little difference, was PV. The frequencies of ABDs and mean age,

age range, and sex ratio of the patients are shown in Table I. A
total of 108 patients (36.4%) were between 60 and 70 years of
age, 100 patients (33.7%) between 70 and 80 years, 76 patients
(25.6%) between 80 and 90 years, and 12 patients (4%) over
90 years.
Patients were divided into three groups for clinical manifestations: skin lesions alone, mucosal lesions alone, and skin and
mucosal lesions together. The patients’ clinical manifestations
are summarized in Table II.
The interval between the onset of disease manifestations and the
final diagnosis ranged from 10 days to 2.5 years, with a mean of
4.5±8.3 months. Table III shows these interval periods in different subtypes of ABDs.
Table IV shows treatment modalities for the ABDs.

Table I. Characteristics of patients with different autoimmune bullous diseases
Number

DISCUSSION
With increasing age, the cutaneous immune system undergoes
some changes, resulting in immune dysregulation, termed immunosenescence. Age-related changes in T cells and cell-mediated immunity may explain why elderly individuals have an
increased risk, not only for infections and malignancies, but also
for autoimmune diseases.8 A vast array of alterations occur in
the cutaneous immune system. At advanced ages, T cells undergo a shift from the naive to the memory phenotype, associSKINmed. 2017;15:175–180

ated with a change in cytokine profile. In addition, they have a
reduced proliferative response after activation, a diminution of T
cell receptor antigen collection, and decreased cytolytic activity.9
Age-related changes in macrophages and keratinocytes lead to
alterations in cytokine production and increased susceptibility
to endotoxins in elderly patients.9
Although the pemphigus group comprised the most common
ABDs in our study, BP represented the most common individual
disease. The ratio of BP to pemphigus has been reported to be

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ORIGINAL CONTRIBUTION

1:8 in ABDs at all ages in Iran,2 but this ratio was 1:1.02 in
elderly patients in our study. The ratio of BP to PV in our study
was 1:0.93. This finding is expected, as the incidence of BP clearly increases with age.
BP is the most common ABD in central and western Europe
(Switzerland,10 Germany,11 the UK,12 France,13 Italy13) and Singapore.14 BP is a disease of elderly patients. Its frequency increases after the age of 70 and it has its highest frequency above the
age of 90.10 In a study in northern Iran, 78% of patients with BP
were 60 years or older.15 In another report, the mean age of onset
of BP was 59.4 years in Iranian patients, lower than in other
countries, where presentation occurred between the seventh and
nine decades.2,10–12,16–22 Likewise, another study in south-western
Iran reported a mean age of 64.1 years.23
BP is more common in women in most countries, except China,
Germany, and Tunisia, where a predominance of men has been reported.24–26 Some studies have reported that the overall incidence
of BP is higher in women, but after the age of 80 years, higher in
men.10,11 The ratio of women to men in our study was 1.6:1, higher than the 1.36:1 that has been previously reported in BP patients
of all ages.2 This may mean that BP is more common in women in
older patients in comparison to younger patients in Iran.
Mucosal involvement is not common in BP. We found mucosal lesions in 11.1% of patients, which was lower than previous
reports from northern Iran and Croatia (31.1% and 16.6%, respectively).15,27

to be the most common ABD worldwide, except in Switzerland,
Germany, the United Kingdom, France, Italy, and Singapore,
where BP is more prevalent.10–14
In Iran and most other countries, PV is the most frequent form
of pemphigus. The PV to PF ratio was 12.1:1 in our study, which
is very close the results of a previous study in Iran.2
In our study, pemphigus was more frequent in women, which
is in accordance with most studies worldwide. Interestingly, a
dominance in men has been reported from Saudi Arabia,29 Kuwait,16 Bangladesh,30 and China.24 Pemphigus can occur at all
ages. It is most frequently diagnosed between the ages of 40 and
60 years. The mean age is between 50 and 60 years in European countries, but in the remaining countries of the world, it
is between 30 and 50 years.13 The mean age of presentation was
reported to be 38, 41.1, 42, 43.3, 45.4, and 46 years in different
studies from Iran.2–7
In our study, 61.1% of patients with PV had mucocutaneous
involvement, 24.7% had skin lesions alone, and 14.1% had
mucosal lesions alone. In addition, involvement of the mucous
membranes were seen in 9% of PF patients. These findings are
similar to the results of a previous study on pemphigus patients
of all ages in Iran.4 It can be concluded that the clinical manifestations of pemphigus in elderly patients are relatively similar to
those in other patients.

Systemic or potent topical corticosteroids represent the best validated treatment options for BP.10 Recent studies indicate that
potent topical corticosteroids are able to control generalized BP
with the same efficacy as oral corticosteroids but with fewer side
effects and lower mortality.28 In our study, the most widely used
treatment (31.4% of patients) was prednisolone plus topical clobetasol. Prednisolone alone and clobetasol alone were used in
28.6% and 22.3% of patients, respectively.

In the present study, the mean duration between onset of disease
and final diagnosis was 9.6 months in PF, longer than in other
ABDs (except epidermolysis bullosa acquisita and linear IgA bullous disease, which, because of the low number of cases, are not
significant). In PF, a delay in diagnosis may be caused by the
more subtle onset of disease, superficial bullae that rupture easily and lead to crusted lesions with no frank blisters or erosion,
seborrheic distribution of lesions, and absence of mucosal lesions
in most patients.

The pemphigus group comprised the most common ABDs in
our study (45.2% PV, 3.7% PF, 0.6% paraneoplastic pemphigus). Among countries where the prevalence of pemphigus was
identified, Iran has the third highest prevalence, after Brazil and
Israel. In Brazil, the endemic form of PF (fogo selvagem) is very
frequent. Although pemphigus can be seen in all races, it is more
common among the Ashkenazi Jewish population.4,13 The incidence of pemphigus in Tehran is approximately 1.6 per 100,000
per year and in Iran 1.0 per 100,000 per year.4 The frequency of
pemphigus was reported to be 86.1% and 78% of ABDs at all
ages by two studies from Iran.2,3 Pemphigus has been reported

Systemic corticosteroid therapy is the main treatment for pemphigus. Immunosuppressive agents are often used for their steroid-sparing effect to reduce the side effects of corticosteroids.
In localized forms of PF, superpotent topical corticosteroids
may be sufficient to control the disease. In our study, prednisolone was prescribed in 98.5% of PV patients, and 100%
of PF patients. The most frequently used immunosuppressive
drug was azathioprine, which was prescribed in 57.4% of patients with PV. Clobetasol was used along with prednisolone
in 36.3% of PF patients with the aim of reducing the dose of
prednisolone.

SKINmed. 2017;15:175–180

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ORIGINAL CONTRIBUTION

Mucous membrane pemphigoid represented 1.3% of ABDs
in elderly patients in our study. Its frequency was reported as
0.7% of ABDs at all ages in Iran,2 1.1% in Tunisia,26 and
0.7% in Kuwait.16 A higher incidence has been reported in
some European countries.18,19 Interestingly, among the patients
with mucous membrane pemphigoid in our study, three patients had mucocutaneous involvement and only one patient
had mucosal lesions alone. This may reflect that most patients
with mucosal involvement are seen by other specialists, such
as dentists, ophthalmologists, and otolaryngologists, and the
incidence of mucous membrane pemphigoid may be underestimated by dermatologists.

Paraneoplastic pemphigus was diagnosed in 0.6% of our patients. It was reported by another investigator that 0.2% of patients may have an underlying malignancy.2 This sounds reasonable, because the older age of our patients resulted in a higher
incidence of malignancy.

Epidermolysis bullosa acquisita and linear IgA bullous disease
each accounted for 0.3% of patients. Other studies from Iran,2
Tunisia,26 and Kuwait16 have confirmed the incidence of epidermolysis bullosa acquisita as 0.5%, 0.6%, and 2.3%, and the
incidence of linear IgA bullous disease as 0.5%, 6.3%, and 7%,
respectively.

Spectrum of Autoimmune Bullous Diseases
in the Middle East: A 15-Year Review
Roger Haber, MD;1 Josiane Helou, MD;2 Carla Habr, MD;3 Roland Tomb, MD, PhD2
Abstract
Characteristics of autoimmune bullous diseases (AIBDs) show wide geographic variation. The aim of this study was to determine retrospectively the characteristics of patients with AIBD admitted to Hôtel-Dieu de France Hospital in Beirut, Lebanon, between 1999 and 2014
and to compare them with those from other areas in the Middle East, the Far East, Asia, North Africa, Europe, and North America. For
the patients with AIBDs and who were hospitalized at a major tertiary referral center between 1999 and 2004, we studied demographics,
diagnosis, length of stay, department/floor, comorbidities, clinical features, in-hospital evolution, diagnostic tests, and treatment. Bullous
pemphigoides was the most frequent bullous disease in Lebanon. This and other findings contrast with those of studies conducted in regional countries. This is the first report of AIBD from the Middle Eastern region. (SKINmed. 2017;15:181–186)

A

utoimmune bullous diseases (AIBDs) are caused by autoantibodies against one or more components of the
basement membrane or desmosomal structural proteins
of the skin. In the pemphigus group, which includes pemphigus
vulgaris (PV), pemphigus foliaceus (PF), IgA pemphigus (IAP),
pemphigus erythematous, and paraneoplastic pemphigus, autoantibodies are directed against desmosomal proteins, resulting
in an intraepidermal loss of cell contact. In the subepidermal
autoimmune bullous disorder, which includes bullous pemphigoid (BP), mucous membrane or cicatricial pemphigoid (CP),
pemphigoid gestationis, linear IgA disease (LIAD), epidermolysis bullosa acquisita (EBA), lichen planus pemphigoides, and
anti-p200 pemphigoid, the antibodies target hemidesmosomal
proteins at the dermoepidermal junction, leading to a subepidermal bullae. Dermatitis herpetiformis and bullous systemic lupus
erythematosus feature subepidermal blistering as well.1 Although
AIBDs occur worldwide and are associated with high morbidity
and mortality rates,2 their relative frequencies and characteristics
show wide geographical variation. Their prevalence in the Middle East is still unknown because of a lack of research on the its
frequency and demographic features. Outpatient and inpatient
data on AIBD are unavailable to date in Lebanon. In this retro-

spective study, we aim to define the spectrum of AIBD over a
15-year period (1999–2014), estimate the incidence of each, describe key demographic features, and compare them with those
reported from other parts of the world.
Patients and Methods
The medical files of 55 patients were reviewed in this descriptive
retrospective study. Patients were admitted for AIBD between
January 1999 and December 2014 to the Hôtel-Dieu de France
Hospital, which is a major tertiary referral center for bullous disease in Lebanon. All patients had been diagnosed on the basis of
clinical findings, histopathology, and direct immunofluorescence
with or without indirect immunofluorescence. Data analysis was
performed using SPSS version 13 (SPSS Inc, Chicago, IL).
Results
A total of 55 patients with documented AIBD were enrolled in
this study. There were 29 (52.7%) men and 26 (47.3%) women,
with age at the time of first presentation ranging from 0 to 94
years. The most frequent AIBD was BP (31 cases [56.3%]), followed by PV (17 cases [31%]), EBA and CP (two cases each

[3.6%]), and PF, LIAD, and IAP (one case each [1.8%]). The
proportion of these blistering diseases is seen in Figure 1.
Among the 31 patients with BP, the mean age of first presentation was 72.3 years (range 52–89 years), and 19 cases were in
men (61.2%). The median time of hospitalization was 6 days.
The most common skin manifestations were cutaneous bullae
(28 of 31), followed by pruritus and/or urticaria (23 of 31), oral
erosions (10 of 31), and dermatitis (3 of 31). Four cases were
attributed to medications (one vildagliptin, one valsartan, and
two furosemide) and resolved after drug cessation. Eosinophilia
was seen in 10 of 31 patients. A total of 21 patients underwent
treatment with oral/intravenous (IV) prednisolone (mean dose
of 0.7 mg/kg/day), 25 patients with topical steroids (mostly topical clobetasol, average of two tubes per day), two patients with
azathioprine, two with mycophenolate mofetil, three with cyclophosphamide, two with methotrexate, one with dapsone, and
one with plasmapheresis. Almost all patients had local wound
care with eosine 2%, chlorhexidine, and silver nitrate 1%. Clinical criteria, rather than serum level of antibody, were used to
guide the therapeutic regimen. Upon discharge, 93.3% of patients had significant clinical improvement and two patients left
against medical advice.

the therapeutic regimen. Upon discharge, 94% patients had significant clinical improvement with drug tapering and one patient
left against medical advice.
There were two cases of EBA and two cases of CP, with a mean
age at presentation of 51 years. One patient was treated with IV
corticosteroids and dapsone, and the other had ocular involvement and was treated with IV corticosteroids and cyclophosphamide. The only case of PF was in an 81-year-old woman who
presented with flaccid bullae and erythematosquamous plaques
and showed improvement with prednisone 1.5 mg/kg/day. Characteristics of patients with different AIBDs are summarized in
the Table. The number of new cases of PB and PV according to
year has been increasing through the past 15 years (Figure 2).

Among the 17 patients with PV, the mean age of first presentation was 63.8 years (range 36–94 years), and seven cases were in
men (41.1%). Median time of hospitalization was 9 days. The
most common skin manifestations were flaccid cutaneous bullae
(16 of 17). Mucosal (oral and/or genital) lesions were seen in
10 of 17 patients. Other common clinical manifestations were
pruritus (5 of 17). Twelve patients underwent treatment with
oral/IV prednisolone (mean dose of 1.5 mg/kg/day), four patients with topical steroids (mostly topical clobetasol, one tube
per day), three with azathioprine, two with cyclophosphamide,
one with methotrexate, and one with cyclosporine. Almost all
patients had the same local wounds care as that for BP. Clinical
criteria, rather than serum level of antibody, were used to guide

Discussion
AIBDs in Lebanon are rare. On average, four new cases of AIBD
are reported by us every year. Still, they are a major cause of
hospitalization. A previous study conducted in the same center
between 1998 and 2007 of 191 patients has shown that bullous
diseases are the second major dermatological disease requiring
hospitalization.3 There was a clear increase in PB and PV in the
past 15 year in this country, probably due to aging of the population and improved diagnostic techniques. Similar results have
been found in the United Kingdom, where the average yearly
increase of BP and PV was 17% and 11%, respectively.4 All diagnoses of AIBD in this study were made upon clinical suspicion
and confirmed with histopathology and direct immunofluorescence, with indirect immunofluorescence being inconsistently
performed. Average overall time for hospitalization was 8 days,
and the most common cause of prolonged hospitalizations was
infectious complications (skin, pulmonary, and urinary) rather
than resistant bullous disease.
BP was the most predominant type of bullous disease in our
study, representing 56.3% of all cases. This is in agreement with
reports from the United Kingdom,4 Germany,5 Singapore,6 and
Switzerland,7 but not from Iran,8 Malaysia,9 China,10 or Kuwait,11 where PV predominates. The higher incidence of BP
may be explained by aging of the Lebanese population as well
as improved diagnostic techniques. Two schemes of treatment
were used for BD. In the first, systemic corticosteroids were
prescribed, and, in the second, immunosuppressive agents and
corticosteroids were given simultaneously, with gradual tapering
of corticosteroids depending on patient response to treatment;
clinical response rather than biologic tests were used to monitor
patient response. Topical steroids and local wound care with antiseptic and silver nitrate were used in almost all cases. The mean
systemic corticosteroid dose was 0.7 mg/kg/day for PB and 1.5
mg/kg/day for PV, and topical steroids were two tubes per day
for PB and one tube per day for PV. No deaths were noted. PreSKINmed. 2017;15:181–186

vious studies on BP have reported incidences between 0.2 and
3 per 100,000 persons per year.4,9,12 In the United Kingdom, a
regional study estimated an incidence of 1.4 per 100,000 persons
per year.13 As expected and similar to previous studies, the rate
of BP progressively and significantly increased with age, with a
mean age of diagnosis of 72.3 years, making BP an emerging
major disease of the growing elderly population in Lebanon. This
is higher than the mean age of BP in Iran, with 65 years,14 Tunisia 67.2 years,15 Poland 67.25 years,16 and Kuwait 65 years,17
but lower than France 83 years,18 Germany 77.3 years,19 and the
United Kingdom 80 years.4 This study also showed that there
was an overall slight male predominance (29 of 55), in contrast
to reports from Malaysia,9,10 Kuwait,11 Switzerland,7 the United
Kingdom,4 and Germany.5 This male predominance applied
to PB (61.2%) but not to PV (41.1%). Of 31 cases of BP, 19
(61.3%) were in men, compared with 35.2% in Iran.14 In Tunisia and China, it is more common in men than women.10,14 In
the United Kingdom, 61% are women.4 In Kuwait, however, the
female to male ratio is 5:1.17 In the United States and Germany,
the incidence in men and women is nearly equal.19,20 Clinically,
cutaneous bullae are the most common initial sign of BP; 90%
presented with bullae, and 73% with pruritus and/or urticaria.
Mucosal lesions were found in 33% of cases of PV, with similar
results in Kuwait17 and in Taiwan.21
BP has previously been reported in association with diseases such
as diabetes, multiple sclerosis, Parkinson disease, ulcerative colitis, and vitiligo.21,22 Fifteen cases with diabetes were found, along
with seven cases of Parkinson disease, four cases of cerebrovascular accidents, and one case of Alzheimer’s disease. Because we
lacked a control population, we are unable to confirm or reject
the association of BP with these diseases that was reported in
previous studies.23–25 Association with malignancies has also been
reported and with higher frequency than with PV, probably because BP patients are generally older than patients with pemphigus.26 Here, three cases (10%) of concomitant cancers were
found. Four cases were attributed to drugs (one vildagliptin, one
aldactone, and two furosemide) and only resolved after drug cessation. BP has indeed been reported in association with various
systemic drugs, of which spironolactone and furosemide are the
most widely recognized.27 Several reports of gliptins inducing BP
have also been reported.28 Eosinophilia was observed in 10 cases
(33.3%), which is in agreement with previous reports.29 Recent
studies indicate that potent topical corticosteroids are able to
control generalized BP with the same efficacy as oral corticosteroids but with fewer side effects and less mortality.30 In this
study, treatment of PB relied on topical steroids (clobetasol two
tubes per day) in 83% of patients, which was associated with
oral/IV prednisolone (mean dose of 0.7 mg/kg/day) in 64.5%

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ORIGINAL CONTRIBUTION

of cases and with immunosuppressants in 29% of cases. Firstline therapy for mild to moderate PB remains topical steroids,
and the high number of patients receiving systemic treatment
(corticosteroids or immunosuppressants) is probably due to the
fact that patients included in this study were hospitalized, thus
having severe cases.
PV was shown to be the second most common bullous (27.8%)
disease in Lebanon and the most common form of pemphigus,
accounting for 90% of all cases of pemphigus (27 of 29). The
next most common subtype was PF (1 of 29) and IAP (1 of 29).
Forms of pemphigus that were not found in this study are pemphigus erythematosus, pemphigus herpetiformis, drug-induced
pemphigus, and paraneoplastic pemphigus. PV was also the
most frequent type of pemphigus in most countries including
India,31 Korea,32 Bangladesh,33 Saudi Arabia,34 Kuwait (in another study),35 Bulgaria,36 Serbia and Montenegro,37,38 Macedonia,39
Croatia,40 Greece,41 Italy,42,43 Germany,44 Spain,45 the United
Kingdom,46 and Singapore,47 but not Tunisia,48 Mali,49 or South
Africa.50 In this study, PV is mostly a disease of middle-aged
adults, with a mean age of 63.5 years, affecting women more
than men (59%). The mean age of onset of BP was 71 years in
the United Kingdom,4 74.6 years in Germany,20 77.2 years in
Switzerland,7 and 66 years in Kuwait.35
Older age at onset of BP was noted in industrialized populations
and further studies are needed to investigate whether this is due
to aging of the population in these countries. Here, 70% of patients with PV had treatment with oral/IV prednisolone (mean
dose of 1.5 mg/kg/day); immunosuppressants were added in
41% of all patients with PV, which corresponds to more severe
cases. All patients had clinical improvement before discharge.
Only one case of PF was reported (1.8% of all BD), in contrast
to reports from Iran where it was the third most common AIBD,
with a frequency of 4.4% in Brazil8 and Tunisia48 where the incidence of PF has been reported to approach endemic levels. CP
was seen in two cases, accounting for 3.6% of all bullous diseases
in Lebanon, which might also be an underestimation of the incidence of this disease due to a referral bias because many patients
are diagnosed and seen by dentists and ophthalmologists. EBA
is one of the rarest forms of AIBD in Western Europe; yet, in
our study, EBA was the third most common acquired bullous
disease, just behind PB and PV.

ever, since mild cases of these diseases may have been missed
clinically or might have been managed by private practitioners
in general outpatient dermatology clinics because the disease is
not generally chronic or severe and therefore may not have been
referred to our center. The same reasons may also be behind the
low frequency of LIAD and IAP, which were only seen each in
1.8% of patients in our study. The cases of paraneoplastic pemphigus, on the other hand, might have been referred or seen by
oncologists.
Study Limitations
Similar to the majority of dermatologic skin diseases, patients
with mild AIBDs are treated as outpatients and do not require
hospitalization. Because our site is a tertiary center, most of the
cases referred are complex or life-threatening. The patients included in this study likely represent the most severe forms of
bullous diseases in this country. In addition, data from this study
were from hospital records rather from a well-designed prospective survey. The lack of a central registry for bullous diseases at
the moment and the presence of another university referral center in Beirut that covers the same patient population made it
impossible in this study to accurately estimate the incidence of
bullous diseases in this country.
Conclusions
This is the first study in a Middle Eastern country to examine the
spectrum of subepidermal AIBDs and compare them with data from
the Far East, Asia, North Africa, Europe and North America. It provides a basis on which future research activities can be built. Studies
with a larger sample size are necessary for achieving additional findings on these diseases and for explaining the ethnic, environmental,
and genetic reasons behind their demographic variations.
References

History of Seborrheic Dermatitis: Conceptual
and Clinico-Pathologic Evolution
Angela Cristina Akel Mameri, MD, MSc;1,2 Sueli Carneiro, MD, PhD;1
Letícia Maria Akel Mameri, MD;2 José Marcos Telles da Cunha, MD, PhD;1
Marcia Ramos-e-Silva, MD, PhD1
Abstract
Seborrheic dermatitis is an inflammatory and chronic disease with a high incidence and prevalence (1% to 3% in the general population,
3% to 5% in young adults, and 40% to 80% in HIV-positive individuals). Although the condition was first described in 1887, its clinical
aspects and clinical forms have still not been well individualized, nor has its etiopathogenesis been fully elucidated. The disease, despite
having clinical features similar to dermatitis, does not have the same histopathologic features or the same progressive clinical behavior. This
contribution reviews the history of seborrheic dermatitis. (SKINmed. 2017;15:187–194)

S

eborrheic dermatitis has often been studied under the
heading of eczema, even though it has been separated
from this group of diseases since its description by Paul
Gerson Unna (1850–1929) in 1887.1 During the 19th century, the term eczema was employed to denote all dermatoses
with a sudden onset, among which are erythema, pemphigus,
erysipelas, and zoster. Since the studies of two English physicians (Robert Willan (1757–1813) and Thomas Bateman
(1778–1821) in 1808, eczema has, however, been regarded as
a separate eruption.2
In 1819, Laurent Theodor Biett (1780–1840) distinguished
two types of eczema—acute and chronic. In 1823, Pierre
François Rayer (1793–1867), in his Traité des Maladies de la
Peau, described for the first time the topographic forms and
evolution of the dermatitis, emphasized its genetic predisposition, and distinguished eczema from other “artificial dermatites” (eczematizations).2
In 1886, during the International Congress of Medicine in
Washington and in his famous lecture “Seborrhoeal eczema,”
subsequently published in the Journal of Cutaneous and Geni-

to-Urinary Diseases (1887),3 Unna distinguished from the
eczema group what he described as seborrheic eczema and
pointed to the scalp as the disease’s starting point. He stated
that it had three characteristics: (1) desquamation (pityriasis capitis or dandruff); (2) crusts (seborrhea sicca capitis);
and (3) a moist nature (eczema chronicum capitis). Unna
described rounded and oval lesions that could merge and
acquire serpiginous and polycyclic forms with defined borders, having yellowish scales that resembled cerumen. They
occurred on the temples, alae nasi, nasolabial furrows, malar
and cervical regions, external auditory canals, upper trunk,
especially the sternal region, perianal region, shoulders, and
arms (but never the elbows). As the lesions were found to be
distributed in areas with a high density of sebaceous glands,
Unna associated seborrhea with sebaceous secretion, even
without an increase in this secretion, and called this form
seborrhea sicca, differentiating it from “oily seborrhea.”
In 1894,4 Unna described what was supposed to be the main
histopathology of the eruption—the spongiotic or spongioid
state of the epidermis—attributed to a coccus (Morococcus),
and considered the edema of the horny layer to be the initial

From the Sector of Dermatology and Post-Graduation Course in Dermatology, School of Medicine and University Hospital,
Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;1 and Private Practice, Vitoria, Brazil2
Address for Correspondence: Marcia Ramos-e-Silva, MD, PhD, Rua Dona Mariana 143/C-32, 22280-020, Rio de Janeiro,
Brazil • E-mail: ramos.e.silva@dermato.med.br

Years later, in 19216 and 1925,7 Achille Civatte (1877–1956)
explained that the initial eczema lesion always started in more
superficial portions of the horny layer, from a small (three
or four) group of Malpighian cells. These would detach and
form a small cavity, immediately distended by serous fluid.
This cavity was replenished by lymphocytes and histiocytes
(mononuclear cell exocytosis). During the development of
spongiosis, parakeratosis, acanthosis, and an inflammatory
infiltrate of round cells, consisting mainly of lymphocytes
and mononuclear cells, would develop in the epidermis.
Civatte believed that the papular nature of some eczemas was
caused by an abundance of edema and especially by cellular
infiltrates.

To group and select some aspects of the disease addressed by
different previous authors, Davies16 called it exudative seborrhea, making the term even more confusing. He presented
erythema as the essential clinical lesion in all forms of exudative seborrhea, and considered that any disorder affecting
the skin (from the acceleration of epithelial growth through
blistering until complete necrosis) could occur in seborrheic
eczema, which would account for the wide variety of clinical
aspects observed, the systemic manifestations, and the relation to or dependence on emotional stress.

In 1928, J.M.H. Macleod (1870–1954) and Geoffrey
B.Dowling (1892–1976),8 using what they imagined to be
a Pityrosporum culture (but was, in fact, a Candida sp. suspension), managed to reproduce seborrheic dermatitis lesions
through intradermal injection or scarification. Only transitional papules were obtained in nonseborrheic volunteers;
however, in 1936 they reproduced the same lesions were reproduced with a Pityrosporum suspension.9 In 1938, Pityrosporum was shown to be a universal resident of the scalp, albeit
in greater numbers in seborrheic patients.10
A 1931 study showed that hormonal imbalance was related
to the high incidence of seborrheic manifestations occurring
at puberty and menopause.
11

In 1938, Unna’s seborrheic eczema was described as a poorly
defined and inaccurate disease, especially in relation to its etiology (Morococcus) and clinical findings (location in areas of a
greater concentration of sebaceous glands).12
Another study in 1938 ranked the seborrheic manifestations
of eczema as infectious, physiologic, and constitutional, considering it to be septic in etiology.13 In the following year,
Percival14 divided the manifestations of seborrheic dermatitis
into three distinct groups: pityriasis capitis (eczematids), infectious flexural dermatitis (intertrigo), and pustular-eczematoid eruptions of hairy areas.
In 1947, seborrheic dermatitis was classified as an eczematid
that could manifest with steatoid figured shapes (Brocq’s mediothoracic seborrhea, Sabouraud’s steatoid pityriasis, Bazin’s
SKINmed. 2017;15:187–194

The patient’s “seborrheic state,”17 was defended at the Annual
Meeting of the American Academy of Dermatology in 1957;
it was believed that the clinical presentation varied according
to the individual and that several systems could be involved,
in particular the endocrine, nutritional, and emotional systems.
Seborrheic dermatitis was placed under the same heading as
psoriasis in 196318 and described as a chronic inflammatory
skin disease characterized by dry, oily, or moist scales, yellowish and crusty macules of various sizes and shapes, and remissions and exacerbations.
The histologic sequential lesions of seborrheic dermatitis were
described in 1966,19 taking a petaloid lesion of the pre-sternal region as a model. Tortuous and dilated capillaries and
edematous papules without epidermal alterations were noted.
Leukocytes appeared afterwards, forming a small group at the
top of the papilla, with disappearance of the grainy layer and
spongiotic edema. In the next stage, with the disorganization
of the suprapapillary area, most cells formed a parakeratotic
scale. The scale was formed as an isolated elevation, while the
Malpighian cells seemed to become organized underneath,
with normalization of the papilla, detachment of the scale,
and emergence of the granular layer, and finally an edematous
papilla with resumption of the process.
In 1967, a study20 discussing the “general concept of seborrheic eczema” placed seborrheic dermatitis within the general
condition of eczema, as a subtype of so-called constitutional
eczema. It was defined as a “sui generis,” scaly erythematodermatosis of an inflammatory nature, with acanthosis, spongiosis, and parakeratotic epidermal changes, a clinical presentation that was regional (classical type) or eruptive (eczematid,

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sensu stricto), and an etiopathogenesis that was subject to a
genetically determined constitutional state.

Others considered it as “a clinical eczematous syndrome,”21 a
“process with torpid evolution able to persist for months or
years and to disseminate into the form of an exfoliative erythroderma,” with the same endogenous nature as atopic eczema,
“appearing on a seborrheic background, perhaps partially due
to the action of certain microbes and, notwithstanding, retaining many affinities with psoriasis.”

Twenty-five skin biopsies from 25 AIDS patients, who presented with “seborrheic dermatitis,” were studied and compared to the same number of skin biopsies from patients with
seborrheic dermatitis who did not have AIDS or its risk factors.24 Findings showed that although the cutaneous eruption
in AIDS clinically looked very similar to seborrheic dermatitis, the histologic aspects were very different.

In 1977, eczematous dermatitis was distinguished from seborrheic dermatitis, based on histopathologic criteria.22 Dermatitis was defined as “inflammation of the dermis;” however, the definition that best matched the term eczema was
the one that associated the description of the clinical aspects
(superficial, erythematous, papulovesiculous, edematous and
crusty process at the beginning, and later purple, scaly, lichenified, and even pigmented) with the histologic certainty
of a primary epidermal lesion, in the form of an intracellular edema, spongiosis, or blistering. Such characteristics are
observed in allergic contact dermatitis, superficial dermatitis
caused by primary agents, superficial viral, bacterial, and fungal infections, and some conditions of unknown cause, such
as nummular eczema.

In 1994, the disease was included in a chapter on eczemas,25
and seborrheic dermatitis was approached as a chronic disease, difficult to conceptualize but with a distinctive morphology, being found in areas with a greater density of sebaceous glands. Seborrheic dermatitis has also been described
as a chronic erythemato-papulous-scaly dermatosis, located
in areas with an increased density of sebaceous glands, that
children and adults not necessarily associated with an increase
in sebum production.26 Others also included seborrheic dermatitis in a chapter on eczema, describing it as a chronic
dermatitis of constitutional character that is associated with
physiopathologic elements of epidermal proliferation.27

The term eczema was found to be dispensable; therefore, the
term “eczematous dermatitis” was replaced by “spongiotic
dermatitis,” and seborrheic dermatitis was considered one
of many spongiotic dermatoses. Chronic seborrheic dermatitis presents follicular horns of ortho- and parakeratocytic
cells, mounds of parakeratosis at the borders of the follicular
infundibulum, long, narrow areas of epithelial hyperplasia,
highly dilated capillaries and venules in the upper portion
of the dermis, and a sparse lymphohistiocytic infiltrate. In
acute lesions, scaly crusts with neutrophils at the border of
the follicular infundibulum, spongiosis, and light epithelial
hyperplasia, as well as a mixed cellular inflammatory infiltrate of lymphocytes, were seen. Histiocytes and neutrophils
around the dilated blood vessels of the superficial plexus were
also observed.22
Seborrheic dermatitis was also described in a chapter on eczema,23 as a constitutional diathesis, with mild to moderately erythematous, desquamative macules with undefined
borders and a central distribution with loose, diffuse scales.
Mild forms affect the scalp, whereas severe forms can affect
the eyebrows, forehead, paranasal folds, retroauricular regions, trunk, interscapular and presternal areas, axilla, pubis,
and inframammary and intergluteal folds. It can also cause
SKINmed. 2017;15:187–194

Giving seborrheic dermatitis the synonyms of seborrheic eczema and eczematid, allows it to be described in a chapter on
erythemato-scaly eruptions. It has a familial predisposition
and immune component, affecting areas rich in sebaceous
glands as well as some intertriginous areas.28
In 2010, seborrheic dermatitis was mentioned along with
other eczematous dermatoses in the book Fundamentos de
Dermatologia as seborrheic dermatitis with a hormonal influence that occurs in areas with an abundance of sebaceous
glands. There is no mention of changes in sebum secretion
when compared to healthy individuals.29 Despite the large
number of Malassezia organisms in the lesions, there is no
proven relation between the number of yeasts and the severity
of the disease.
In its 131 year history, seborrheic dermatitis has been described any number of times. The disease has various presentation,2,30–35 including psoriasiform and pityriasisform
patterns. Although some authors consider that it can develop into erythroderma,36 it does not, according to Unna’s
descriptions, affect the extremities. As to infantile seborrheic
dermatitis, it may resemble atopic dermatitis, when a family
history of atopy is obtained. In relation to infantile seborrheic
dermatitis, the clinical manifestations are of a difficult differential diagnosis in relation to atopic dermatitis, including

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in relation to the itching and familial history of atopy. Many
children finally diagnosed as having infantile seborrheic dermatitis did not at first have this diagnosis confirmed during
the evolution of the disease.34,37

tion of the form in which the disease manifests according to its

Despite the recognition of dermatologic lesions (erythema,
papules, scales), there has not yet been an objective descrip-

moderate and severe in terms of the immunohistochemical

severity. The Table shows the characteristics of seborrheic dermatitis as described by different authors since 1886. Recently,
some authors have separated the clinical manifestations into
profile of the seborrheic dermatitis.38,39 The disease, however,

Table. Seborrheic Dermatitis Characteristics as Given by Different Authors Since 1886
Author

Spongiotic or spongioid state of the
epidermis. Edema of the horny layer
as the initial factor in the process.
Perinuclear edema and swelling of the
basal cells and vacuoles in squamous
cells are secondary to the interstitial
edema

Sabouraud5

1902

Pityriasis

Same lesions described by Unna, with the exception of
dry and scaly lesions (considered by Sabouraud as forms
of psoriasis)

Spongiosis and vesiculation resulting
from the papillary dermis blood vessel
transudate (Sabouraud’s exoserosis),
which spreads into intercellular spaces
in the basal layer immediately above
the papilla, and then to the squamous
layer

Civatte,6,7
Darier et al15

1924

Eczematide

Same lesions described by Unna, but without clinicalpathologic consensus, with a great variability of clinical
expression and evolutionary inconsistency. A variety of
eczema

Primary histological lesion
consisting of small vesicles, the result
of a spongiotic process in the cells of
the squamous layer. Interspersed with
mononuclear cells

Considered seborrheic eczema as described by Unna as
Not described
inaccurate in its clinical delimitations, as it encompassed
clinical features of other entities already recognized by
other dermatologists as individual conditions.
Questioned the anatomic basis of the disease (there
were no lipids in the epidermal cells) and did not accept
Morococcus as the causative agent

Spectrum of papular, scaly, and crusty lesions,
characterized by a mild chronic inflammatory reaction
in the seborrheic areas, dry lesions or papular-scaly, and
moist and crusty in folds

Not described

Rabello and
Fraga21

1970

Seborrheic
eczema

"Clinical eczematous syndrome"—torpid evolutionary
process that can persist for months or years and may
be generalized as an exfoliative erythroderma. Same
endogenous nature as atopic eczema, "appearing on
a seborrheic background due to the action of certain
microbes, and nevertheless, keeping many affinities with
psoriasis"

Not described

Ackerman22

1977

Seborrheic
dermatitis

Not described

Acute lesions: squamous crusts
containing neutrophils at the edge
of the follicular infundibulum, mild
spongiosis, mild epithelial hyperplasia,
and a mixed cellular inflammatory
infiltrate of lymphocytes, histiocytes,
and neutrophils, perivascular and
dilated in the superficial plexus.

Plewig and
Jansen26

1999

Seborrheic
dermatitis

Chronic papular-erythematous-scaly dermatosis, located
in areas with greater density of sebaceous glands,
affecting children and adults, and not always associated
with increased production of sebum on the scalp, face,
and trunk

Not described

16

Continued

can present with a mild form (light clinical inflammation),
the classically recognized moderate form (more accentuated
clinical inflammation), and a severe form (an intense clinical
inflammatory reaction).
Seborrheic dermatitis is one of the most common dermatologic manifestations in HIV infection; it is included in the
spectrum of idiopathic lesions and should be carefully evaluated in high-risk patients.40 Its incidence and severity are directly linked to the stage of the HIV infection and are conSKINmed. 2017;15:187–194

versely correlated to the absolute CD4 T cell count.41,42 As
the disease advances and progresses, the lesions of seborrheic
dermatitis spread and worsen.43 It is known that the HIV virus destroys regulatory T cells44 and is possibly involved in the
pathogenesis of seborrheic dermatitis.
FINAL CONSIDERATIONS
There are few facts but much speculation regarding seborrheic
dermatitis, a disease that is morphologically distinct from eczema but has been without clinically/pathologically defined

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Table. Seborrheic Dermatitis Characteristics as Given by Different Authors Since 1886 (Continued)
Author

Year

Name

Clinical aspects

Histopathologic aspects

27

Cestari et al

2006

Eczemaseborrheic
dermatitis

Not described
Macular-papular lesions, erythematous or
yellowish, dull, delimited, and covered by scales of a
greasy nature, distributed throughout seborrheic areas
(scalp, face, presternal region, and interscapular, axillary,
and anogenital folds). Scalp almost always affected, very
often alone. Early forms such as dandruff (pityriasis
capitis) may progress gradually with the appearance of
erythema, thicker scales, and transgression of the scalp’s
borders. May be erythema, desquamation, and outer ear
and retroauricular fissures. On the face,
involvement occurs on the inner side of the eyebrows,
glabella, nasolabial groove, bridge of the nose, and
paranasal region; also common are erythema and
marginal scaling of the eyelashes. On the trunk, petaloid
lesions, often in interscapular and presternal regions
(erythematous, desquamative papules, initially follicular
that originate annular pattern lesions, with thin central
desquamation and higher borders). Axillary,
anogenital, and inframammary folds are the most
involved (intertrigo), with an erythematousdesquamative aspect sharper at the center

Sampaio and
Rivitti28

2007

Seborrheic
eczema and
eczematide

Chronic, frequent, recurring, noncontagious eruption
in areas rich in sebaceous glands and eventually some
intertriginous areas. The lesions are erythematousscaly and affect the scalp, face, nasogenian groove and
glabella, retroauricular area, median portions of the
chest (Brocq’s mediothoracic dermatitis), and pubic and
axillary regions. On the scalp, "dandruff" is described
as a minimal form of the disease (steatoid pityriasis).
Authors also consider blepharitis and external auditory
canal "eczema" as clinical manifestations of
seborrheic dermatitis

Chronic dermatitis with areas of
parakeratosis, mild to moderate
acanthosis and spongiosis, exocytosis
and a mononuclear infiltrate in the
dermis

Accioly
Filho29

2010

Seborrheic
dermatitis

Described together with other eczematous dermatoses
such as seborrheic dermatitis with hormonal influence,
occurring in areas with many sebaceous glands, but
without reference to the change in the secretion of
sebum compared to healthy individuals. Despite the
large number of Malassezia organisms in the lesions,
refers to no proven relation between the number of
yeasts and disease severity

Not described

patterns since its initial description by Unna; instead, the
topography of the disease is the factor, making the differential diagnosis from other dermatoses, among which is atopic
dermatitis. The natural course of this chronic disease has not
yet been described. There are, in addition, questions to be
answered: Are the clinical forms static or do they evolve from
mild to severe? Do the variations in clinical picture (localized or disseminated lesions) fall within the same form (mild,
SKINmed. 2017;15:187–194

moderate, or severe), or are there patients who change from
one clinical form to another?
In fact, Pityrosporum is an aggravating factor for the disease,
but the fungus is not always found in the lesions. The term
“individual susceptibility” is related to human leukocyte antigens and T lymphocytes; this shows that there is still an insufficient understanding of the disease’s physiopathogenesis.

Pityrosporum is a fungus which (is):
Causative of seborrheic dermatitis in rare patients.
Causative of seborrheic dermatitis in some patients.
Causative of seborrheic dermatitis in many patients.
Causative of seborrheic dermatitis in most patients.
Contributes to causation but is not causative of
seborrheic dermatitis.

4. Clinical seborrheic dermatitis associated with HIV
positive status: (Choose as many as apply. All, some,
one, or none of the answers may be correct.)
a. Is histologically quite different from other cases of
clinical seborrheic dermatitis.
b. Occurs with an incidence directly related to the
stage of the HIV infection.
c. Occurs with a severity directly related to the stage
of the HIV infection.
d. Occurs with an incidence inversely related to the
CD4 lymphocyte count.
e. Occurs with a severity inversely related to the CD4
lymphocyte count.

Smoking and the Skin
Uwe Wollina, MD
Abstract
Smoking has been identified as a habit that carries great health risks. This review focuses on the consequences of smoking for skin diseases,
treatment responses, and outcome. Diversification of the tobacco industry has led to new challenges, and careful documentation of risks
for healthy skin is a continuing challenge. (SKINmed. 2017;15:197–202)

S

moking affects several aspects of health and increases the
risks for cerebrovascular insults or cancers such as lung
and breast cancer. Cigarette smoke contains thousands
of chemical components, including nicotine. Cigarette smoke
disrupts the mitochondrial respiratory chain and induces reactive oxygen compounds, leading to apoptosis and cell damage.
Smoking reduces life expectancy and quality of life. It can also
negatively influence the normal function of healthy skin or modulate skin diseases and their response to treatment.1
SKIN AGING
Aging in general has been linked to telomere-associated cellular
senescence. Oxidative stress contributes to telomere shortening,
and because smoking increases oxidative stress, it is therefore involved in exogenous aging of the skin.2
Tobacco smoking is an independent risk factor for facial wrinkles as a sign of aging,3 and extrinsic aging by ultraviolet irradiation is aggravated by smoking.4 Smoking is also a risk factor for
eyelid sagging.5
Smoking contributes to premature hair graying in men: a longer than 5 pack-year history of smoking carries an odds ratio of
1.61. Smoking is the third most important factor after a positive
family history and obesity, but is not related to severity of graying.6
Smokers develop microvascular dysfunctions in the skin. Postischemic percentage change from baseline, power spectral density in myogenic vasomotion, postischemic percentage increase of

endothelial-dependent vasomotion, and sympathetic-dependent
vasomotion have all been shown to be reduced in smokers compared with never-smokers.7
SMOKING AND WOUND HEALING
Smoking temporarily decreases tissue oxygenation. The inflammatory healing response becomes attenuated, fibroblast proliferation and migration are diminished, and collagen synthesis
is downregulated. Cessation of smoking leads to an improved
healing response within 4 weeks, but restitution remains incomplete.8 Cessation of smoking for less than 3 weeks, however, does
not reduce the risk of postoperative complications.9
Smokers have an increased risk for tissue necrosis (odds ratio
3.60), delayed healing and suture dehiscence (odds ratio 2.07),
surgical site infection (odds ratio 1.79), and wound complications (odds ratio 2.27).10 In reconstructive dermatosurgery,
flap necrosis is another unwanted adverse effect of smoking.11
Wound healing is delayed in smokers undergoing nail matrix
phenolization.12
INFLAMMATORY SKIN DISEASES

Eczema
The term eczema refers to a range of inflammatory diseases including atopic dermatitis, allergic and irritant contact dermatitis, and seborrheic dermatitis. In a survey from West Sweden,
its patient-reported lifetime prevalence was 40.7% and its point
prevalence 11.5%, with a female predominance. Smoking increased the risk for coexistent asthma and rhinitis.13

Tobacco smoking increases the risk for foot eczema with an odds
ratio of 1.19.14 The Odense Adolescence Cohort Study on Atopic
Diseases and Dermatitis (TOACS) calculated a 1-year prevalence
of hand eczema in young adults of 14.3%; hand eczema was confirmed by clinical examination in 6.4%. In contrast to foot eczema, the authors could not find an association with smoking.15
A recent meta-analysis confirmed that tobacco smoking was not
a risk factor for hand eczema. The authors concluded that they
could not exclude that smoking might have an impact on the
course of this disease, but that further studies were needed.16 The
role of smoking habits on hand eczema has been analyzed in a
study of 516 adult housewives; interestingly, smokers were mainly
affected by milder disease than was seen in nonsmokers.17

Psoriasis
Psoriasis is a chronic inflammatory disorder with cutaneous and
extracutaneous manifestations. Oxidative stress contributes to
the extent and severity of the disease. Current and past smoking
increase the risk for psoriasis with an odds ratios of 1.78 and
1.62, respectively.18
In one study investigating smokers and nonsmokers with psoriasis,
smokers had a higher Psoriasis Area and Severity Index score. Serum total oxidant status, total antioxidant capacity, and oxidative
stress were higher in psoriasis patients than in healthy controls.
There was no statistical difference between smokers and nonsmokers. Arylesterase levels were significant lower among smokers.19
Smoking increases the incidence of psoriasis among men and women. The more cigarettes that are smoked per day, the higher the risk.
The relative risk was 2.29 for current smokers who smoked more
than 25 cigarettes per day. A longer duration of smoking and higher
number of pack-years also increased the risk. Cessation of smoking was associated with a decreased risk over time.20 One possible
link between smoking and psoriasis could be the serotonin pathway, which affects chemotaxis, leukocyte activation, proliferation,
and cytokine secretion.20 Patients with psoriasis have a higher risk of
periodontal disease. Smoking increases the risk for severe periodontal disease sixfold.21 Smoking has negative impact on functional outcome in patients with psoriatic arthritis.22 Eventually, smoking may
contribute to the increase cardiovascular risk reported for patients
with psoriasis.23

Rosacea
Rosacea is an inflammatory disease characterized by a disturbance
in centrofacial blood flow regulation and the innate immune
system. In a cross-sectional study, smoking was more prevalent
among rosacea patients than controls. In particular, erythematotelangiectatic rosacea was associated with active smoking.24
SKINmed. 2017;15:197â&#x20AC;&#x201C;202

Acne vulgaris
Acne vulgaris is a disease that affects more than 80% of the general population after puberty. In a study of more than 27,000
young men aged 21 to 22 years, the prevalence of severe acne was
significantly lower in active smokers than nonsmokers. There was
an inverse relationship between the number of cigarettes smoked
per day and the prevalence of acne.25 As a proof of concept, these
authors suggested a trial with nicotine patches, but this has not
yet been performed.
On the other hand, postadolescent acne among 26 women aged
25 to 50 years seems to be associated with smoking. Almost 73%
of women with comedonal postadolescent acne were smokers,
compared with fewer than 30% of those with papulopustular
type.26
In conclusion, acne is not uniform in its response to smoking,
and smoking cannot be advised as possible acne treatment.

Acne inversa (hidradenitis suppurativa)
Acne inversa is a severe and debilitating chronic inflammatory
disease, and smoking is the major risk factor for acne inversa.
Current smokers have an odds ratio for the disease of 4.34,
which is higher than for obesity, another well-established risk
factor. Past smoking carries an odds ratio of 6.34.27
Smoking is common among individuals with acne inversa. A
total of 92.2% of 212 acne inversa patients in a recent Danish
study were smokers. Remission of disease was reported by 40%
of nonsmokers, compared with 29% of active smokers.28 These
results suggest that smoking may contribute to ongoing inflammation and a reduced response to treatment.
AUTOIMMUNE CONNECTIVE TISSUE DISORDERS
AND PEMPHIGUS

Lupus erythematosus
Lupus erythematosus is an autoimmune disorder with manifestations in various organs, including the skin. In a retrospective analysis of 405 lupus patients, more patients with discoid
lupus and lupus tumidus were smokers. The odds ratio for
lupus tumidus was 4.5, and for discoid lupus was 2.05.29 Current smokers had higher disease activity, as measured by the
Cutaneous Lupus Erythematosus Disease Area and Severity
Index, than never-smokers and past smokers. This was also
associated with a decreased quality of life. Never- and past
smokers responded better to oral antimalarials.30 This has
also been suggested by a recent European Society of Cutaneous Lupus Erythematosus study involving 1002 patients.31 A

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meta-analysis including 1398 patients with cutaneous lupus
suggested a twofold lower percentage of patients achieving an
improvement of their cutaneous lesions with oral antimalarials among smokers.32
In the Canadian SLE cohort study of 1346 patients, current
smoking was associated with active systemic lupus eruptions
(odds ratio 1.63), and current and/or past smoking increased the
risk of discoid lesions (odds ratio 2.36), photosensitivity (odds
ratio 1.47), and cutaneous involvement score (odds ratio 1.50).33
A recent meta-analysis suggested that smoking per se increases
the risk of SLE with an odds ratios between 1.76 and 2.09.34 The
Japanese Kyushu Sapporo SLE (KYSS) study found that current
smoking increased the risk of systemic lupus erythematosus significantly (odds ratio 3.06).35

Systemic sclerosis
Systemic sclerosis is the second most common classical autoimmune connective tissue disorder. Smoking has a strong negative
impact on systemic sclerosis. The Canadian Scleroderma Research Group conducted a study of 606 scleroderma patients,
which concluded that smoking has a cumulative and irreversible
negative effect on cutaneous involvement.36 A French retrospective study on ischemic digital ulcers in scleroderma stated that
active smokers had significantly more surgical amputation and
osteitis than nonsmokers.37 It has been suggested that smoking
has a negative and permanent impact on the outcome of scleroderma-associated interstitial lung fibrosis.38
On the other hand, smoking does not increase the risk for scleroderma, although it has a negative impact on disease course and
severity.39 Current smoking increases the risk of Raynaud’s phenomenon but only in men.40
Clinical studies suggest a lower prevalence of smoking among
patients with pemphigus than healthy controls. On the other
hand, a study of 70 pemphigus patients suggested that smokers
achieve more remissions within 2 years of treatment compared
with nonsmokers.41
VASCULAR DISORDERS

Behçet’s disease
Behçet’s disease is a multiorgan disorder with vasculitic features.
Behçet’s patients with the GSTM1 null glutathione-S-transferase
polymorphism who were smokers had a decreased risk for developing papulopustular lesions and chronic arthritis. Conversely,
risk for large-vessel vasculitis was increased among smokers.42
SKINmed. 2017;15:197–202

Thrombangiitis obliterans
Thrombangiitis obliterans is a painful segmental inflammatory vascular disease affecting small- and medium-sized arteries of the hand and feet in tobacco users of younger ages. The
disease progresses to claudication, skin ulcers, and gangrene.
Cessation of tobacco use is essential for any successful intervention.43
ORAL MUCOSAL LESIONS
Oral mucosal lesions have been found in about 70% of tobacco
users. The most prevalent lesion was melanosis (43.3%), followed by leukoedema (27.0%). Leukoplakia (3.17%) was the
most commonly seen premalignant lesion.44 The prevalence is
higher among tobacco chewers than tobacco smokers.45
Tobacco smokers show larger oral areas of oral melanosis compared with nonsmokers. This argues that there is increased melanin production among tobacco users. The condition is known as
smoker’s melanosis.46
White oral lesions are more frequent among tobacco smokers
than nonsmokers, but the difference did not reached significance in a study from Qatar. Patients who chewed or smoked
paan displayed significantly more white and red lesions. A total
of 8.9% of these patients presented oral precancerous lesions.47
Last but not least, smoking is a dose-dependent risk factor for
the development of oral and oropharyngeal squamous cell carcinoma.48
Complex aphthosis, ie, recurrent oral and genital aphthosis
without systemic disease, can be triggered by cessation of smoking in active smokers. Nicotine replacement therapy has therefore been suggested, but this has not yet been studied in trials of
this disorder.49,50
SKIN CANCER

Melanoma
Melanoma is a neoplastic disease of pigment-producing melanocytes and carries a significant morbidity and mortality. Cox
proportional hazards regression analysis was used to evaluate the
association between smoking and melanoma development. The
incidence rate was lower in current smokers than in nonsmokers
independent of sex. The death rate from melanoma was lower
in current smokers (only for men) and past smokers (for both
sexes) than nonsmokers.51 The lowered risk was most significant
for head and neck melanomas.52 The cause of the reduced risk or
melanoma, however, remains unclear.

199

Smoking and the Skin

May/June 2017

REVIEW

Nonmelanoma skin cancer

Betel quid chewing is a traditional habit in Asia. In the last decade, commercial products also containing tobacco have become
popular in India and other countries. Betel quid carries a number of health risks, including oral submucous fibrosis and oral
squamous cell carcinoma. The risk of oral cancer is further increased by tobacco.63,64

Nonmelanoma skin cancer is frequently seen in white populations. The most common skin cancer is basal cell carcinoma. A
16-year prospective study in Queensland, Australia, has investigated the possible link between smoking and basal cell carcinoma. There was a nonsignificant but inverse association between
current smoking and development of basal cell carcinomas, although this was not the case for patients who had smoked for
longer than 18 years and smoked more than 15 cigarettes per
day. Among past smokers, the relative risk for basal cell carcinoma was not changed.53 These findings confirmed the results
of a meta-analysis.54 In contrast to this, another study from the
United States found a slightly increased risk for basal cell carcinoma among smokers versus nonsmokers, with a relative risk of
1.06.55 These data do not indicate a causal relationship between
smoking and reduction of cancer risk.

The waterpipe (shisha or hookah) has become quite popular
among young adults in developed countries. The associated toxicological hazards are not identical to those of smoking cigarettes,
but waterpipe smoking is not a “healthier” alternative.65

On the other hand, smoking significantly increased the risk of
cutaneous squamous cell carcinoma, with an odds ratio of 1.52
in one study,55 while another study calculated a relative risk of
1.19 for smokers versus never-smokers.54

References

The diversification of the tobacco market is also visible in the
recent economic success of electronic nicotine delivery systems,
including standard and nicotine-free electronic cigarettes. The
aerosol, with its fine particles, additives, and solvents, bears significant health risks.66 Careful observation and documentation
of health risks in dermatology is needed.67

Arsenic methylation in smokers may also contribute to the development of arsenic precancerous lesions in areas with a higher
arsenic content in drinking water.56
VIRAL INFECTIONS
Human papillomavirus infection has a worldwide prevalence of
9% to 13%. Smoking is associated with a higher incidence and
prevalence of human papillomavirus infection, with an odds ratio of 1.5. Smoking also supports persistence of infection. The
incidence and recurrence of anogenital warts are significantly
increased among smokers,57 but a correlation could not be established between smoking and the size of anal warts in HIVinfected women.58
OUTLOOK AND CONCLUSIONS
Smoking may exert various negative effects on skin diseases,
aging, and wound healing. Smoking habits are not stable; for
instance, a continuous decline in smoking prevalence has been
observed in Sweden in the last 30 years. However, there has
been a steady increase in the use of moist snuff called snus.59 It
has been hypothesized that snus could be a treatment alternative in otherwise resistant pyoderma gangrenosum.60 A case of
angioedema caused by snuff due to type I allergy to tobacco
has been reported.61 In an animal study, even short-term exposure to snuff significantly increased the risk of random flap
necrosis.62
SKINmed. 2017;15:197–202

1. Smokers, compared to never-smokers, are at an
increased risk for development of:
a. Extrinsic ageing caused by ultraviolet light exposure.
b. Eyelid sagging.
c. Facial wrinkling.
d. Microvascular dysfunction in the skin.
e. All of the above.
f. None of the above.

4. Studies have shown that smokers, compared to
never-smokers, are at increased risk to develop:
a. Basal cell carcinoma(s).
b. Malignant melanoma(s).
c. Squamous cell carcinoma(s).
d. All of the above.
e. None of the above.

2. Risk of which of the following adverse outcomes of
dermatologic surgery is/are increased in smokers
versus never-smokers? (Answer as many as apply.
Some, one, none, or all of the lettered responses may be
correct.):
a. Delayed healing.
b. Flap necrosis.
c. Surgical site infection.
d. Suture dehiscence.
b Tissue necrosis.
f. Wound complications.

Fine and Benign, Until It Becomes Malignant:
The Enigmatic Keratoacanthoma
Ann M. John, BA; Heather Holahan, MD; Parmvir Singh, BS; Hee J. Kim, BS;
Marc Z. Handler, MD; W. Clark Lambert, MD, PhD
“When she was good she was very, very good, And when she was bad she was horrid.”—Henry Wadsworth Longfellow (1807–1822)

K

eratoacanthoma (KA) is a tumor that characteristically
arises as a single nodule, grows rapidly, and regresses
quickly.1 It presents as a crater-shaped exophytic nodule
with a central keratin plug. Rapid growth occurs within 6 to
8 weeks, followed by a stable stage lasting a few months. Rapid regression occurs in 4 to 6 weeks.1 During the initial rapid
growth phase, the histology is similar to a well-differentiated
squamous cell carcinoma (SCC). During the mature stage, histologic analysis shows well-differentiated squamous epithelium,
encompassing the lesion with a keratin-filled core. Papillomatosis, acanthosis, eosinophilic keratinocytes, and the presence of
horn pearls also mark the condition. An inflammatory infiltrate
of lymphocytes and histiocytes is present. During the regression
stage, the keratinocytes shrink, and granulation tissue and fibrosis are present. This stage is marked by an inflammatory infiltrate
of Langerhans’ cells and CD4-positive T lymphocytes.2

excision. Excision is a risk factor for recurrence due to trauma to
the skin; to avoid this, healing by secondary intention is recommended. Chemotherapy, radiotherapy, phototherapy, and observation have also been used. In addition, laser, electrosurgery,
and cryosurgery can be used. With multiple or larger lesions,
oral retinoids or systemic chemotherapy may be employed. One
study also suggested supplementary use of topical 5-fluorouracil cream for more desirable cosmetic results.3 Regardless of the
treatment, the rate of recurrence is 3% to 5%.4

KA has been associated with several cutaneous conditions, including Ferguson-Smith disease, Muir-Torre syndrome, xeroderma pigmentosum, hypertrophic lichen planus, nevus sebaceous,
and prurigo nodularis. In addition, KA is difficult to distinguish
from SCC. The keratin core is specific for KA; however, central
necrosis of SCC can lead to a similar appearance. Histologically,
KA has a central keratin plug composed of large cells with pale
eosinophilic cytoplasm. Since it was first reported, the relationship between KA and SCC has been heavily debated, primarily
due to the similar histology. The potential for misdiagnosis of
SCC as KA warrants treatment.2

CASE REPORT
A 67-year-old Caucasian woman developed a crateriform keratotic lesion on her right cervical region (neck; Figure). Histologically, the lesion was diagnosed as a KA, with the deep margin
not quite clear. No further treatment was undertaken, because
the clinician considered the entity benign; however, it recurred
as an invasive SCC requiring four separate surgical procedures
over the next 6 months to insure clear margins. There has been
no metastasis 1 year after initial presentation.

Treatment of KA depends on the appearance, location, and size
of the lesion. First-line therapy is usually an elliptical or full-shave

The rapid growth of KAs may lead to local destruction. In particular, there are three forms that are locally destructive—muti-

Although KA is almost always benign, there have been a few
reports of malignant transformation or behavior with metastases
and/or invasion. This leads to the question of what distinguishes
a malignant KA requiring aggressive therapy from a benign KA.
Here, we present a case of a benign-appearing KA that exhibited
malignant behavior.

PERILS OF DERMATOPATHOLOGY
within a KA, likely due to the similar risk factor of ultraviolet
irradiation for both cancers. Second, SCC can be easily confused
with KA, specifically the infundibular and infudibulocystic variants. Finally, carcinoma metastasizing to the skin can present as
a KA-like lesion. As such, we join many of our colleagues in
recommending that all KAs be reported from the dermatopathology laboratory as “KA-like squamous cell carcinoma” and be
treated with surgical excision.
References
1 Schwartz RA. Keratoacanthoma: A clinico-pathologic
enigma. Dermatol Surg. 2004;30:326–333.
2 Davis BA, Monheit GD, Kline L. Metastatic skin cancer presenting as ptosis and diplopia. Dermatol Surg.
2006;32:148–158.

lating KA, aggregated KA, and KA centrifugum marginatum.
While rare, these variants cause local infiltration, and may have
persistent invasive growth with absent regression leading to severe defects. For instance, there have been previous reports of
local invasion into the periosteum and muscle, requiring amputation of a limb; destructive infiltration of the left buccal region
(cheek), nasal cartilage, cribiform plate, and conjunctiva; and
growth on the right nasal wall, extending through the ala and
nasal vestibule.5–7 In addition to local invasion, there have been
reports of perineural invasion, presenting with lesion extension
into facial muscles, cranial nerves, and cavernous sinus, metastasis to the parathyroid gland and lymph nodes, and recurrence
of lesions.8 Perivascular invasion and metastasis have also been
reported.9
Because the benign nature of KA is questionable, each KA must
be thoroughly examined and investigated. First, SCC can arise

he revolution of molecular biology is enabling us to
fit disparate pieces of a jigsaw puzzle into a coherent
picture. This commentary will detail how overlapping
features of multiple hereditary infudibulocystic basal cell carcinomas (BCCs), Gorlin syndrome (nevoid BCC), familial multiple meningiomas, and medulloblastomas are linked together
by SUFU mutations in the sonic hedgehog pathway.
CLINICAL CONUNDRUMS OF
INFUNDIBULOCYSTIC BCC
Controversy has always surrounded the diagnosis of the infundibulocystic BCC (IBCC), notably whether it is a true malignancy, or whether it is identical to the benign basaloid follicular
hamartoma. A study comparing 36 cases of basaloid follicular
hamartoma to 22 cases of IBCC, using routine microscopy and
staining for CK20, found that most cases were indistinguishable, supporting the argument that these lesions are identical,
and likely benign.1

The original contribution on multiple hereditary infudibulocystic BCCs detailed members of two families with multiple
IBCCs. Each patient had multiple facial papular lesions, with
none displaying jaw cysts or palmar pits, thereby distinguishing
this syndrome from nevoid BCC.2 A subsequent report was of a
67-year-old man who started developing BCCs at age 50. Numerous shallow pits were present on his palms and fingers. No
ondontogenic keratocysts were appreciated. Biopsies of several
of the facial papules revealed BCCs with follicular differentiation, while others demonstrated infiltrative BCCs. A palmar pit
biopsy showed basaloid proliferation but no BCC. There was
no family history of similar lesions. Genetic mutational analysis for PTCH was negative. The authors speculated that patients

with generalized basaloid follicular hamartoma, nevoid BCC,
multiple hereditary infudibulocystic BCC, and multiple trichoepitheliomas all represented abnormalities of the same signaling
pathway.3 Future studies would prove them correct.
CASE HISTORIES
A 55-year-old woman with facial papules (diagnosed as benign
folliculosebaceous hamartomas) and dysmorphic facies (macrocephaly, hypertelorism, prognathism) had two children (each
with a different father) succumb to medulloblastomas in infancy.
The patient stated that her father and a grown son shared her
dermatologic features. Sequencing studies of the patient revealed
a splice-site mutation of intron 6 of SUFU.4
A woman in her 60s started to develop approximately 60 facial
and vulvar lesions that first appeared around 50 years of age. No
palmar pits or jaw cysts were appreciated. Her medical history
was remarkable for a meningioma. Biopsies of the facial lesions
were consistent with IBCC. Her daughter had similar facial lesions. The patient was given a trial of vismodegib, but did not
respond to therapy after 9 months of treatment; the drug was
discontinued. Whole-exome sequencing demonstrated a conserved splice-site mutation in one copy of the SUFU gene in all
tumor and normal tissue samples.5
Medulloblastomas are seen in 5% of patients with nevoid BCC.4
Sporadic and familial medulloblastomas and meningiomas have
been associated with SUFU mutations.6,7
THE SONIC HEDGEHOG PATHWAY AND SUFU
BCCs are primarily driven by the sonic hedgehog pathway. In a
study of 293 BCCs, 85% of BCCs harbored mutations in sonic

hedgehog pathway genes: PTCH1 (73%), TP53 (61%), SMO
(20%), and SUFU (8%). Additionally, 85% of the BCCs harbored additional driver mutations in other cancer-related genes
such as MYCN, KRAS, and HRAS.8 The SUFU (suppressor of
fused homolog) protein acts as a tumor suppressor by binding
to and modulating the function of the transcription factor Gli.
SUFU has a downstream position in the sonic hedgehog pathway.

be able to target SUFU mutations precisely, thereby obviating
the snafus that have a potentially devastating impact.
References

Presumably, SUFU mutations are less disruptive to the pathway
than are upstream mutations in PTCH1 or SMO.5 This could
explain why IBCCs tend to be more indolent and unresponsive
to vismodegib, and may even be considered benign by some authorities.
CONCLUSIONS
When confronted with a patient with multiple facial papules,
consider performing a biopsy—should the diagnosis be IBCC,
basaloid follicular hamartoma, or multiple trichoepitheliomas,
inquire about a personal or family history of similar cutaneous lesions and central nervous system tumors (meningiomas,
medulloblastomas). The family history may be negative, as this
situation may occur with a sporadic mutation in the context of
an otherwise autosomal dominant disorder. With cutting-edge
molecular studies, we can now appreciate how these syndromes
overlap, resulting in variable phenotypic expressions of the sonic
hedgehog pathway. Recognition of these clinical-molecular correlates will allow identification of patients at risk for life-threatening complications of SUFU mutations. Future discoveries will

Picturing in Dermatology—From Wax
Models to Teledermatology, Part I
Eve J. Lowenstein, MD, PhD
Izena duen guzia omen da. (That which has a name exists.)—Basque proverb

M

auricio Goihman-Yahr (Caracas, Venezuela) spoke
on Dermatology and vision: A homo sapiens approach. Graphics and sculpture have been used since
prehistoric times, with their messages sometimes unclear and
perspective-dependent. Interestingly, dermatology was one of
the first subspecialties to individuate, perhaps due to its unique
reliance on vision to transmit knowledge of diagnosis through
media such as atlases.
Eve J. Lowenstein (Brooklyn, NY) discussed The largest mass poisoning in history: Arsenic in well water in Bangladesh. Arsenic in
drinking water worldwide constitutes the largest cause of mass
poisoning in history, dwarfing Chernobyl. Before the 1970s,
Bangladesh had one of the highest infant mortality rates in the
world, secondary to cholera and diarrheal diseases from contaminated hand-dug wells and ponds. While millions of tube wells
were sunk in the 1970s to 90s to create “safe” water and save
lives, the unintended consequence of this “colossally successful
safe-water program” was the exposure of millions to arsenic in
drinking water, in turn posing the highest cancer risk ever found
via environmental exposure. With profound effects on health
and culture, the full extent of the damage in Bangladesh remains
to be determined.
W. Clark Lambert (Newark, NJ) presented Why most of what
you were taught in medical school about cancer etiology is wrong.
He described how the current cancer dogma is incorrect. Carcinogenesis is not the consequence of sequential mutations but
rather simultaneous events. While the Pasteur effect describes
the cessation of fermentation in the presence of oxygen, this effect is ignored by the Warburg effect—cancer cells’ tendency to
ferment despite the presence of oxygen.

THE TOOLS
Robert Thomsen (Los Alamos, NM) spoke next about The melancholy instance of leprosy in England: A dermatologic engraving
as evidence in a legal proceeding in 1824. Three atlases published
in 19th century show beautiful images of leprosy presentations,
but some of the pictures had other uses. The images were used in
defense of a man against whom a legal suit had been brought for
breach of marital promise.
Daniel Wallach (Paris, France) discussed Moulanges in Paris. He
gave a brief history of the 19th-century era of l’Hôpital SaintLouis and its world-famous school of dermatology. In recognition of the hospital’s excellence in dermatology, a museum library was built in 1889 for the First Congress of Dermatology. It
has more than 4000 downloadable images that can be accessed
for free virtually under the history of health images and portraits
section at http://www.biusante.parisdescartes.fr.
Robert Pariser (Norfolk, VA) presented Practical imaging in dermatology: Kodachrome, Ektachrome, and Fujichrome. He brought
his own projector to show the slides, as in past days. He described
the fascinating history of the rise and fall of Kodachrome, which
had been patented in the 1920s, and how it gained popularity due to user-friendliness even for the amateur, affordability,
and faithfulness to the image, as well as a long shelf life. Its use
peaked in the 1960s and 70s, being replaced by the competing
Ektachrome in the 1980s, Fujichrome in the 1990s, and finally
digital photography in the 21st century.
Michel Lavery (Dublin, Ireland) spoke about Teledermatology:
The practice of providing skin care remotely using technology. Store
and forward, real-time and hybrid forms available with different

The 2017 meeting of the History of Dermatology Society was held on March 2 in Orlando, FL. The main topic was to look
into the ways skin disease can be presented.
From the Department of Dermatology, SUNY Health Science Center at Brooklyn, Brooklyn, NY
Address for Correspondence: Eve J. Lowenstein, MD, PhD, Department of Dermatology, SUNY Health Science Center at
Brooklyn, Box 46, 450 Clarkson Avenue, Brooklyn, NY 11203 • E-mail: evlow13@yahoo.com

practice models were reviewed. The history of technology-based
remote medical care began with late 19th-century use of Morse
code and evolved with the interactive televized transmission of
information. Since the early 1990s and with the advent of universal mobile phone use, teledermatology has blossomed. The
increased wait time to access a dermatologist promotes the need
for further establishment of this as an integral format for skin
care, especially in rural areas.
A FAMOUS ILLUSTRATOR AND SCULPTor
Branka Marinovic (Zagreb, Croatia) recalled the famous illustrator Carl Heitzman (1836–1896). Born in what is today Croatia,
he studied dermatology, surgery, and pathology, becoming famous
as an illustrator and physician. His illustrations are not only artistic, but also show an excellent understanding of dermatology. He
emigrated to New York and developed a large practice there.
Natalie Curcio (Nashville, TN) presented Enrique Zofio Davila (1835–1915), a master sculptor of the Olavide Museum in
Madrid. He began as an anatomic sculptor, later focusing on
dermatologic sculpture. Although he likely made thousands of
sculptures, many were lost in fires and through time, with about
650 sculptures extant and on display today. His techniques remain undisclosed, even a century after his death. Zofio made all
the sculptures in the Olavide, a museum established in honor of
the father of Spanish dermatology, Jose Eugenio Olavide (1836–
1901), that remains open to the public today.
ATLASES
Robert Norman (Tampa, FL) talked about the atlas Delineations
of Cutaneous Disease by Thomas Bateman. Robert Willan (1757–
1812), the London physician, is recognized as the founder of our
specialty. He was the first to propose a rational naming standard,
based on the appearance of a skin disorder. In the treatise On Cutaneous Diseases, Willan was the first to classify skin diseases from
an anatomic point of view. When Willan died in 1812, leaving his
student Thomas Bateman to continue and expand on his work.
In 1813, Bateman published A Practical Synopsis of Cutaneous
Diseases According to the Arrangement of Dr Willan, and in 1817
he published an atlas called the Delineations of Cutaneous Disease.
Willan, together with Bateman, provided the world with its first
attempt at taxonomic classification of diseases affecting the skin.
Mark Valentine discussed Louis Duhring’s (1845–1913) Atlas
of Skin Diseases. Born into an affluent family in Philadelphia,

SKINmed. 2017;15:211–213

Duhring received his medical degree at the University of Pennsylvania and then trained for 2 years in Vienna, Paris, and London with some of the world’s pre-eminent dermatologists. His
most important contribution to dermatology was the identification in 1884 of dermatitis herpetiformis (Duhring’s disease). His
well-received atlas was published in 1876. It had 36 color plates
and was the first of its kind in the United States. This self-funded
project was pricey (the cost of the completed atlas was steep, at
$25.00—about $600 at today’s value). This atlas focused on skin
disease, commonly seen by the general practitioner.
Mark Bernhardt (Fort Lauderdale, FL) presented Photographic
illustrations of skin diseases by George Henry Fox (1846–1937).
Fox is quoted as having said, “The study of skin diseases without cases or colored plates is like the study of osteology without
bones, or the study of geography without maps.” His atlas images were of such quality as to become the gold standard of the
time.
Gerd Plewig (Munich, Germany) presented Atlas der Hautkrankheiten by Keizo Dohi (Ishiwata). Dohi (1866–1931), was
a monumental Japanese dermatologist. He was first trained in
surgery, later turning to dermatology, with several educational
trips to famous European departments. His atlas, printed in
1903–1910 in installments, was 120 pages long with 50 chromolithographic plates, and was printed fully in 1910. Few copies
of this extraordinary atlas can be found today.
The final presentation, delivered by Shoko Mori, highlighted
the Atlas of Disease of the Skin, including an epitome of pathology and treatment by Franz Mracek (1848–1908), the American edition of which was edited by Henry W. Stelwagon
(1853–1919). Mracek and Stelwagon’s atlas gives us insight
into the common dermatologic diseases seen during the 19th
and early part of the 20th centuries. These colored depictions
closely resemble the clinical picture, perhaps even better than
early photographs. The illustrations/engravings were very
true to life and form a well-executed, convenient, and wellpriced reference, making them accessible to the physician in
general practice.
CONCLUSIONS
While these presentations varied in scope, they provided a way
of unification of our sense of the importance of history when
viewing the skin.

A 37-year-old woman attended the dermatology outpatient clinic because of recent hair loss from the eyebrows and axillae. Her past medical history revealed mild generalized erythema and hyperpigmented papules and plaques since childhood. On dermatologic examination,
there were flat-topped, purple to brown hyperkeratotic lichenoid papules and linear plaques on the elbows, trunk, and buttocks, some of
which coalesced into hyperpigmented reticular plaques on the axillae, neck, and groin. Mild erythema was noted. There was thinning and
loss of hair of the eyebrows; severe loss of hair was noted in the axillae and genital regions (Figure 1). One of the lichenoid papules was
biopsied. The specimen showed histopathologic findings of focal parakeratosis, irregular acanthosis, an increased granular layer, and focal
vacuolar degeneration of the basal layer. Necrotic keratinocytes were also observed. Hyalinization and abundant melanin in the papillary
dermis and marked congestion of blood vessels were noted (Figure 2). Clinicopathologic correlation of the case was consistent with keratosis lichenoides chronica (KLC). (SKINmed. 2017;15:211–213)

K

LC (Nekam disease), also called lichen ruber moniliformis and lichen ruber acuminatus, was first described
by Moritz Kaposi (1837–1902) in 1895 in a patient
with linear, warty lesions.1 Louis Nekam (1868–1957) described the disease as a separate entity in 1938.2 The term keratosis lichenoides chronica was used for the disease by Margolis
et al. in 1972.3

In a detailed review by Boer, a remarkable number of KLC patients reported in the literature were in fact patients with lichen
simplex chronicus, lichen planus, or lupus erythematosus; however, a few patients, who were diagnosed as KLC, showed similar clinical characteristics, including widespread lesions, which
appear as scaly and seborheic dermatitis–like on the face, with
keratotic papules and plaques forming linear or net-like shapes
on the extremities and trunk.4 The oral lesions appear as aphthae, erythematous papules on the mucosa, and white patches
on the tongue.4,5 Our patient had typical lichenoid papules on
the extremities and net-like hyperpigmented plaques on the neck
and axillae, accompanied by hair loss of the eyebrows, axillae,
and genital regions; however, the oral mucosa was not involved.

Histopathologic findings may show a patchy lichenoid infiltrate
along the basal layer and around the infundibula and acrosyringia, leading to permanent hair loss, as in our case.6
The differential diagnoses include other lichenoid dermatides
such as lichen planus, lichenoid drug eruptions, lichen striatus,
lichenoid keratosis, pityriasis lichenoides, and lichenoid graftvs-host disease. Although KLC is mainly a lichenoid eruption,
the presence of parakeratosis, alternating atrophy and acanthosis, numerous plasma cells, and dermal telengiectasies are clues
for diffentiating this entity from other lichenoid dermatoses.
Additionally, there may be focal atrophy of the epidermis, necrotic keratinocytes, uneven acanthosis, and keratotic plugs in
the infundibula. Histologic features can be very similar to those
of lichen planus, although in KLC the epidermis may show areas
of acanthosis as well as atrophy; these may be covered by focal
parakeratosis with hypogranulosis under the parakeratotic areas.
Follicular plugging often accompanies the lichenoid reaction.
Additionally, telengiectasia and proiminent blood vessel congestion can be observed, as in our case.7

Figure 1. Flat-topped, purple-brown hyperkeratotic papules on the elbows, extensor aspects of the lower extremities and
feet, with erythematous and hyperpigmented reticular plaques on the axilla and neck. Additional thinning and loss of
hair of the eyebrows and axillary region.

KLC may be divided into two subgroups according to disease onset. Childhood-onset KLC may be familial with possible autosomal recessive inheritance. Facial involvement
along with alopecia of the eyebrows and eyelashes are more
common findings in childhood-onset KLC.7 KLC facial lesions are mainly erythematous and purpuric in children,
SKINmed. 2017;15:211–213

Historical Diagnosis and treatment
Diagnosis and treatments have advanced over the past century. This feature depicts
conditions from a collection of stereoscopic cards published in 1910 by The Stereoscopic
Skin Clinic by, Dr S. I. Rainforth.

A 91-year-old Hispanic man with a diffuse large B-cell lymphoma of the stomach that was currently being treated with immunosuppressive therapy was referred for evaluation of a biopsy-proven squamous cell carcinoma in situ (SCCis) on the left mid-region of his
back. The lesion had apparently been present at birth and had recently started to itch, become red, and progressively enlarge. (SKINmed.
2017;15:215–216)

C

utaneous examination of the left mid-region of the back
showed a 12.5 cm × 8.5 cm well-demarcated plaque
with variable colors including areas that were red, tan,
and brown (Figures 1 and 2). The texture also varied: there were
thin patches with minimal epidermal change and thicker scaling
plaques within the tumor.
An incisional biopsy was performed to exclude the possibility of
malignant melanoma and extramammary Paget’s disease. Pathology showed atypical keratinocytes with large nuclei throughout
all layers of the epidermis (Figure 3). Immunohistochemical
studies for antibodies to HMB-45, anti-tyrosinase, and CK7
were all negative. The diagnosis of SCCis was confirmed. Scattered aggregates of dermal melanophages and focal hyperpigmentation of basal keratinocytes were also present. These pathologic changes accounted for the hyperpigmentation observed
clinically.

scaling plaque.1 The risk of progression to invasive squamous cell
carcinoma is estimated to range from 3% to 5% for nongenital
SCCis.2,3
The clinical presentation of our patient’s tumor proved to be a
diagnostic challenge due to the color variegation and the history—albeit probably inaccurate—of congenital onset. An incisional biopsy was performed to confirm the diagnosis and to rule

Treatment options were discussed with the patient and his family. It was decided to treat the tumor with curettage and desiccation. At 1-year follow-up, there was no tumor recurrence.
DISCUSSION
SCCis is a common intraepidermal malignancy. It usually presents in sun-exposed areas as a gradually enlarging, erythematous

Figure 1. A large well-demarcated plaque with variable
colors located on the left mid-region of the back.

From the Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX;1 and the Department of Dermatology, University of California San Diego, La Jolla, CA2
Address for Correspondence: Deborah MacFarlane, MD, Department of Dermatology, The University of Texas MD Anderson
Cancer Center, 1400 Pressler, Unit Number 1452, Houston, TX 77030 • E-mail: dmacfarl@mdanderson.org

CASE STUDY
inconvenience of their use for the patient; in addition, there
was concern regarding the potential of systemic absorption with
5-fluorouracil 5% cream and failure of therapy (secondary to his
immunosuppressed status) with imiquimod 5% cream.
Our patient’s tumor was successfully treated with curettage and
desiccation. The patient tolerated the procedure well . The treatment site rapidly healed without any complications.
Conclusions
Pigmented SCCis is an infrequent clinical variant of nonmelanoma skin cancer. Giant SCCis is an uncommon presentation of
this cutaneous malignancy. The development of such a giant pigmented SCCis as in our patient is indeed rare, and provided us
with not only a diagnostic dilemma, but also a therapeutic challenge. The diagnosis was confirmed by repeating the pathology
evaluation on an additional incisional biopsy tissue sample with
routine hematoxylin and eosin staining, and also immunohistochemical studies. Successful management, using curettage and
desiccation, was well tolerated by the patient; the treatment site
healed rapidly and there has been no recurrence of the cancer.

Management of our patient’s SCCis proved to be a challenge
because of the tumor’s size. Giant SCCis is uncommon;9,10 however, giant SCCis has previously been successfully treated with
radiotherapy9 or combination photodynamic therapy and imiquimod cream10 after other treatment modalities failed.

The approach to treating our patient’s tumor was also influenced
by his elderly age, his cognitive ability, and his immunosuppressed status resulting from his lymphoma and its treatment.
Surgical excision was considered impractical due to the tumor
size. Topical treatments were not recommended because of the

Edward L. Keyes Resident Contest
for Outstanding Case Reports
13th World Congress of the International Academy of Cosmetic Dermatology
Dubrovnik, Croatia June 28–July 1, 2018
Abstract deadline: March 31, 2018
To be awarded for the best Case Report submitted by a physician in training (resident, fellow,
or registrar) for presentation at the 13th World Congress of the International Academy of
Cosmetic Dermatology in Dubrovnik, Croatia from June 28–July 1, 2018.
We invite you to submit original Case Reports that reflect the presentation of new ideas and
original observations to the Academy membership and other attendees of the Congress. The
case may be medical, surgical, and cosmetic (or combined) in nature.
The author whose abstract obtains the highest score during the review process will
receive a scholarship by the IACD to present the full paper at the 13th World Congress
of the International Academy of Cosmetic Dermatology in Dubrovnik, Croatia from
June 28-July 1, 2018. The scholarship will provide reasonable travel expenses, lodging
for 3 nights, the Congress registration fee, and a basic spending stipend.
Please submit your case report abstract via email to vrosic@medicine.bsd.uchicago.edu before
noon, CDT, March 31, 2018. The abstract should be no longer than 2,500 characters including
spacing. Material that was previously presented, published, or submitted for publication
should not be offered. Applications will be graded based upon the educational value of
the abstract and the extent to which it presents new and significant work. The Review
Committee strongly recommends that abstracts have an organized, coherent, well-thoughtout, and complete presentation. Please note that no paper submitted for consideration will
be eligible if it has already been, or is in consideration for, publication elsewhere at any
time prior to the meeting. The winner(s) agree to publish their outstanding case report(s) in
SKINmed: Dermatology for the Clinician, an official publication of the International Academy
of Cosmetic Dermatology. By submitting your paper for consideration, you give SKINmed:
Dermatology for the Clinician first-rights of refusal for publication through December 31, 2018.
The applicant must be in training at the time of the Congress presentation.
All applicants will receive e-mail notice of the Resident Case Report Review Committee’s
decision by May 1, 2018.
Vesna Petronic-Rosic, MD, MSc
Chair, Resident Contest Committee
Professor and Chief
The University of Chicago Pritzker School of Medicine
Section of Dermatology
Tel: +1.773.702.6559
vrosic@medicine.bsd.uchicago.edu

A 46-year-old woman with a 30 pack-year smoking history presented with a worsening eruption on the left cheek that failed to improve
with metronidazole gel. The cutaneous eruption spread to most of her face and did not respond to a brief tapering course of prednisone.
During the initial evaluation at our institution, approximately 6 weeks after the onset of the cutaneous eruption, the patient had erythematous, crusted plaques on her face and scalp (Figure 1A); they were also present on the V-area of the anterior aspect of the neck and upper
region of the chest, the shoulders, and the arms, with isolated lesions on the trunk and legs. Her oral mucosa had erythematous erosions on
the hard palate and gingivae. A review of systems revealed pain and burning of her skin lesions, but no muscle weakness or other systemic
clinical manifestations. The differential diagnosis included autoimmune connective tissue disease, pemphigus foliaceous, sarcoidosis, lichen
planus, phototoxic drug eruption, and eczema herpeticum. (SKINmed. 2017;15:218–220)

DISCUSSION
Cutaneous lupus erythematosus (CLE) in the setting of malignancy
rarely is reported, although an association between subacute CLE
(SCLE) and malignancy has been described.1 In 2005, Chaudhry
et al1 reported a case of SCLE that preceded the diagnosis of laryngeal squamous cell carcinoma, adding to 11 other reports of SCLE
occurring as a paraneoplastic phenomenon (2 of the 11 patients
had small cell lung carcinoma). Since then, five other patients with
SCLE in the setting of malignancy have been reported.2–4
Paraneoplastic dermatosis has two major diagnostic criteria: (1)
the dermatosis arises after development of the malignant tumor,
but it does not necessarily precede tumor diagnosis; and (2) the
dermatosis and malignant tumor should follow a parallel course.5
Our patient met both criteria because her cutaneous disease preceded the diagnosis of the underlying malignancy, and both conditions improved after radiochemotherapy.
The risk of lung cancer increases in persons with systemic lupus
erythematosus, and smoking is an important predictor of lung
cancer development in systemic lupus erythematosus.6 A recent
Swedish epidemiologic study of CLE patients (with or without
systemic lupus erythematosus) nationwide described a nearly
fourfold increased risk for certain cancers (buccal, lymphoma,

respiratory, nonmelanoma) compared with a control cohort
without CLE;7 moreover, CLE is worse in current smokers than
past smokers and never-smokers.8

Figure 1. (a) Erythematous, hyperkeratotic, crusted
plaques and papules on the head, neck, and upper chest.
(b) Dramatic improvement of the cutaneous eruption
after two cycles of radiochemotherapy.
SKINmed. 2017;15:218–220

We cannot completely exclude the simple concurrence of two
separate entities (discoid lupus erythematosus and lung cancer in
a smoker) in our patient, but their abrupt onset (within 6 weeks
of each other) and simultaneous response to radiochemotherapy
suggests paraneoplastic discoid lupus erythematosus as the most
likely diagnosis. In cases of paraneoplastic SCLE, there is a possible stimulatory tumor antigen as the trigger for development
of SCLE.1 In this scenario, cutaneous lesions may be due to episodic antigen expression by the tumor, and hence may reflect the

antigen load, rather than the absolute tumor mass;1 this may
explain why the latency period can vary depending on the size
and type of malignancy.
Conclusions
In most of the previously reported cases, the cutaneous eruption
was responsive to cancer therapy (eg, surgery or chemotherapy,
or both). In our patient, there was a clear association between
tumor shrinkage and improvement of cutaneous lesions. We
suggest that the effect of cancer treatment on the skin was attributable to the tumor response, although we cannot completely
exclude the possibility that chemoradiotherapy directly affected
the discoid lupus erythematosus lesions.
References
1 Chaudhry SI, Murphy LA, White IR. Subacute cutaneous
lupus erythematosus: A paraneoplastic dermatosis? Clin
Exp Dermatol. 2005;30:655–658.

An otherwise healthy 36-year-old Caucasian woman, without prior history of atopic dermatitis or eczema, presented to an outside dermatologist with a generalized, severely pruritic eruption involving the entire body except the face. One month previously, she had used a 50%
trichloroacetic acid tattoo removal solution on a blue-colored tattoo on the medial aspect of the left ankle. The patient’s eruption persisted
for 7 months, and after several attempts to slowly taper her prednisone dose, she presented to our institution. On physical examination,
there was a 3-cm erythematous, lichenified plaque surrounding the tattoo (Figure). On the trunk and upper regions of the arms, there were
scattered, 1- to 2-cm, nummular patches and plaques. Biopsy of a truncal lesion revealed spongiotic pustules with a mixed dermal infiltrate
and scattered eosinophils, consistent with subacute spongiotic dermatitis. (SKINmed. 2017;15:221–222)

O

ne week after discontinuation of a 3-week oral prednisone
taper, patch testing demonstrated neomycin 3+, bacitracin
3+, cobalt 1+, and carba mix 1+. As has been previously
reported, “In tattoo reactions, patch testing may not be effective
since the inflammatory response is triggered by material within the
dermis. This is unlike contact dermatitis, in which antigen-presenting cells within the epidermis trigger the reaction.”1 We believe this
is the reason the patch test reaction to cobalt was weak (1+) rather
than exuberant.
Despite the patient being treated with topical steroids, she continued to experience flares of her pruritic eruption. Considering the positive patch testing result for cobalt and the patient’s
history of chemical peel-induced erosive dermatitis in the cobalt-containing blue tattoo, the diagnosis of probable systemic
sensitization to cobalt was made. The tattoo was removed with
a two-step staged excision by plastic surgery. At 4 weeks after
complete excision, her diffuse eruption had completely resolved.
Subsequent rechallenge with neomycin and bacitracin did not
result in a systemic flare.

Local reactions have been reported to occur secondary to hypersensitivity to tattoo pigment, with blue ink tattoo reactions
being linked to cobalt.1 Several cases of reactions to cobalt in
tattoos have been previously described, including a contact urticaria, granulomatous reaction, and sarcoidal reaction, all of
which were localized to the blue ink of tattoos.2–4
There are several reported cases of systemic tattoo reactions to
other compounds contained in different pigmented inks, but
to our knowledge this is the first case of systemic hypersensitivity to cobalt. In our case, a chemical peel and subsequent
erosions likely unmasked or triggered sensitization to cobalt,
and subsequently resulted in a systemic allergic reaction. We
hypothesize that exposure of pigment in the dermis along with
inflammation induced by an irritant peel resulted in antigen
recognition, uptake, and maturation of dermal dendritic cells,
initiating a subsequent delayed-type hypersensitivity reaction
that potentially led to systemic response, as seen in Id reactions.5

From the Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI;1 the Department of Dermatology,
Scott and White Health, Temple, TX;2 the Department of Dermatology, Intermountain Healthcare, Sandy, UT;3 and the Department of Dermatology, University of San Diego, San Diego, CA4
Address for Correspondence: Edit B. Olasz MD, PhD, Department of Dermatology, Medical College of Wisconsin, 9200 West
Wisconsin Avenue, Milwaukee, WI 53226 • E-mail: ebolasz@mcw.edu

A 45-day-old infant was brought by his parents to the dermatology outpatient department with chief complaints of asymptomatic, depigmented lesions that had been present on his skin since birth. On mucocutaneous examination, large rhomboid-shaped depigmented
macules were noted on the abdomen and lower extremities bilaterally (Figure 1). A depigmented macule was present on the forehead, with
white hair (leukotrichia; a “developing forelock”) (Figure 2). Three hyperpigmented lesions (café-au-lait macules [CALMs]) were also noted
on the chest (Figure 1a). There was no history of consanguinity, and the family history was negative. The infant was otherwise normal for
his age. A diagnosis of “piebaldism with CALMs” was made, and his parents were counseled about the disease and its progression, and possible treatment options as the child grew. They were also informed about a currently unquantifiable risk of future development of Legius
syndrome or neurofibromatosis type 1 (NF1), and were counseled for regular follow-up. (SKINmed. 2017;15:223–225)

P

iebaldism is a rare, autosomal dominant genodermatosis
secondary to the congenital absence of melanocytes in
skin and hair, resulting in depigmented macules on the
forehead, chest, abdomen, and extremities. A white forelock is
seen in 80% to 90% of patients. Piebaldism is an uncommon
disorder, with an estimated incidence of less than 1 in 20,000.1
Most cases of piebaldism are caused by a number of mutations
in the KIT proto-oncogene on chromosome 4q11-12, which
encodes the cellular receptor tyrosine kinase for the mast cell/
stem cell growth factor (the “Steel factor”), an embryonic
growth factor. The mutations cause defects in the development
or migration of melanoblasts from the neural crest during early
embryonic life, which result in an absence of melanocytes in affected areas of skin and hair. Some cases of piebaldism are now
also known to occur due to mutation of the SLUG (also known
as the SNAI2) gene on chromosome 8q11. This gene encodes
the slug protein (a zinc-finger neural crest transcription factor),
which is also critical for the development of human melanocytes.2 Patients with piebaldism, however, are known to present
with other hyperpigmented lesions, some of which have been
present since birth.

Patients with piebaldism may present with three peculiar types
of hyperpigmented lesions. First are the hyperpigmented macules most commonly interspersed through the congenital depigmented lesions; these usually develop late in the disease process.1
Much less commonly, CALMs, and axillary and inguinal freckling (identical to that seen in and leading to a clinical diagnosis
of NF1) is present. Recently, there has been a case of piebaldism
with atypical freckling on the limbs, but sparing the axillae and
inguinal regions.3
There have been a number of case reports of association of
piebaldism with NF1 (von Recklinghausen’s neurofibromatosis), as patients with piebaldism, multiple CALMs, and axillary/inguinal freckling (Crowe sign) also fulfill two of the
seven updated diagnostic criteria of the National Institutes
of Health Consensus Statement that are needed to clinically
diagnose NF1.4,5 NF1 is one of the classical autosomal dominant neurocutaneous syndrome of tumor formation associated with characteristic pigmentary anomalies. The gene for
NF1 is situated on chromosome 17q11.2 and encodes the
“neurofibromin” protein, which, as it can downregulate Ras
activity, acts as a suppressor of tumor activity. It is of par-

CASE STUDY
dard as the sensitivity of molecular diagnosis of NF1 is 95%,
and 5% to 10% mutations, being microdeletions in the NF1
gene, may be missed by standard polymerase chain reaction–
based testing. They also state that mutation of the KIT gene,
which controls the proper development of bone marrow–derived mast cells, may prevent neurofibroma formation, and
thus “neurofibromas are not an appropriate clinical feature
for the diagnosis of NF1” in cases of piebaldism.7
Legius syndrome (OMIM #611431) is a new disease entity
that was described in 2007. It closely resembles NF1 but can
be clinically distinguished by the absence of tumors, such as
Lisch nodules, neurofibromas, or optic gliomas, and also by the
absence of the NF1 gene mutation. Clinical features of Legius
syndrome, caused by an autosomal dominant mutation of the
SPRED1 gene on chromosome 15q13.2, include CALMs, axillary/inguinal freckling, macrocephaly, Noonan-like facies, and
learning problems.8 A recent report has shown an association
of piebaldism with CALMs, and intertriginous freckling, and
postulate that the defective KIT tyrosine kinase in piebaldism
leads to inadequate phosphorylation of SPRED1. This results
in loss of inhibition of the Ras/MAPK pathway, resulting in a
“Legius-type” phenotype, and does not indicate an association
between piebaldism and NF1.9

Figure 1. Large depigmented macules on (a) the ventral
aspect of the trunk and (b) right leg. Café-au-lait macules
are present on the chest.

Some observers, however, have hypothesized that a separate, as
yet unidentified, locus may be responsible for hyperpigmented
macules in piebald individuals, which may explain the phenotypical variations in patterns of pigmentation and freckles.3
The recent novel missense mutation (heterozygous missense
c.2431T>G mutation in exon 17 of the KIT gene in the proband and the affected son) in a Chinese family may well support
the notion that CALMs and intertriginous freckling of piebaldism may be considered components of pigmentary anomaly in
piebaldism, and may not necessarily represent a coexistence of
NF1,2 except possibly in the case reported by Tay.5

Figure 2. Depigmented macule on the forehead, with
leukotrichia.

Conclusions

ticular interest to note that in all cases of an association of
NF1 and piebaldism that have been reported to date, tumor
formation is conspicuous by its absence, except in a 15-yearold Chinese girl in whom Lisch nodules and scoliosis were reported.5 Some workers remain skeptical about whether a true
association exists between these two disorders, and have stated that a diagnosis of NF1 should not solely be based upon
pigmentary features.6 Another group, however, consider the
National Institutes of Health clinical criteria to be gold stanSKINmed. 2017;15:223–225

Our patient, presenting with three CALMs of significant size,
might in future develop NF1, or Legius syndrome, or neither. Around 40% of patients with NF1 have presented with a
“CALMs-only subtype”,10 a condition also referred to as NF6
(CALMs-only NF6 of Riccardi and Eichner).5 From a review of
the multiple reports that associate piebaldism with NF1, piebald
patients usually do not develop some of the more morbid complications seen with NF1, particularly tumor formation,6 and an
altered, less rigorous health care management plan should thus
be considered appropriate for them.

“Neurofibromatosis” Made by Lotte Volger in 1928
in the Clinic for Dermatology Zurich. Museum of Wax
Moulages Zurich, www.moulagen.ch
Courtesy of Michael Geiges, MD

SKINmed. 2017;15:223–225

225

Association of Piebaldism with Café-au-Lait Macules

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A 45-year-old Chinese man had begun to show asymmetry of the face 30 years previously. Subsequently, he developed visual extinction
of the right eye, slight numbness, and weakness of the left extremities. Simultaneously, multiple atrophic brownish patches occurred on
his side. He denied prior trauma or tick bites at those sites. There was no report of preceding redness, induration, or a history of trauma.
The atrophic lesions extended and enlarged slowly. Ten years previously, some brownish patches with normal texture had appeared on the
right side of the trunk. There was no further progression of the lesions. In November 2010, the patient consulted our department for the
final diagnosis and prognosis of his disease. He did not suffer from epileptic seizures and had no history of a tick bite or Lyme disease.
(SKINmed. 2017;15:227–229)

O

n examination, the patient had hemiatrophy of the
right mandibular area and atrophy of the right side
of the tongue. The right mandibular angle was more
obtuse than the left. Hyperpigmentation was also noted along
the right side of the chin (Figure 1A). The left extremities were
shorter, the left hand and foot being shorter and narrower
than their right-sided counterparts. A few depressed brownish
patches were observed on the left shoulder, left arm, back, and
lumbar region (Figure 1B), and the medial region of the left
thigh (Figure 1C). In the centers of these patches, variciform
superficial veins with no redness or induration could be seen
clearly. Cranial nerve functions and extraocular movements
were normal, and the pupils were of equal size. Right visual
acuity was decreased but the optic fundus was normal. Muscle
strength of the left extremities measured 4/5 on a manual muscle testing scale.

did not reveal any abnormalities. Histopathologic examination
of the biopsy specimen from the hyperpigmented lesion in the
right mandibular area showed normal epidermis with increased
pigment granules in the basal layer, perivascular mononuclear
infiltration of the atrophic dermis, and subcutaneous adipose
tissue, in more superficial layers of the skin than usual (Figure
2). Magnetic resonance brain images taken on August 14, 2007
and January 14, 2011, respectively, characterized by an increased
atrophy and decreased extension of the right white matter intensity, showed progress of the disease. Based on the clinical and
histopathologic findings, the patient was diagnosed with crossed
total hemiatrophy and atrophoderma of Pasini-Pierini (APP) on
the back. Intramuscular injection of benzathine benzylpenicillin, once a week, contiguously for 3 weeks, was prescribed.

Laboratory examinations produced normal results except for positive antinuclear antibody (speckled pattern, titer 1:320). In particular, investigations for rheumatic disease were unremarkable.
Antibody screening for immunoglobulin G and M to Borrelia
burgdorferi was performed, and the results were negative. Electrocardiography, abdominal ultrasonography, and a chest x-ray

Crossed total hemiatrophy implies facial atrophy and contralateral atrophy of the trunk and extremities. A few cases have
been reported.1 APP is an uncommon dermatologic condition
of unknown etiology, characterized by asymptomatic, violaceous
brownish discolored patches, and usually presenting as one or
more sharply demarcated depressed lesions.2

DISCUSSION

From the Department of Dermatology, the Third Affiliated Hospital of Suzhou University, Changzhou,1 and the Department
of Dermatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing,2 China
Address for Correspondence: Wen-yuan Zhu, Department of Dermatology, the First Affiliated Hospital of Nanjing Medical
University, 300 Guangzhou Road, Nanjing 210029, China • E-mail: zhuwenyuan@yahoo.com

Figure 1. Clinical findings. (a) Hyperpigmentation was noted along the right side of the chin. A few brownish patches
were apparent on the left shoulder and arm, back, and lumbar area (b), and the medial region of the left thigh (c). In
the centers of these patches, variciform superficial veins with no redness or induration could be clearly seen.

(a)

(b)

Figure 2. Normal epidermis with increased pigment granules in the basal layer, perivascular mononuclear infiltration
of the atrophic dermis, and subcutaneous adipose tissue in more superficial layers of the skin than usual. (Hematoxylin and eosin stain; (a) ×40; (b) ×100.)

Progressive facial hemiatrophy (PFH), or Parry-Romberg syndrome, is a sporadic and poorly understood disease of unknown
etiology. Different reports about the onset of PFH after Lyme
disease led to a controversial discussion about a possible association.3 Some findings indicated a possible relevance of autoimSKINmed. 2017;15:227–229

munity in the pathogenesis of the disease.4 The distribution of
PFH along the branches of the trigeminal nerve, which carries
a great number of sympathetic fibers, underscores the assumed
importance of the sympathetic nervous system.5 Considerable
controversy and confusion remain regarding whether PFH is a

228

Crossed Total Hemiatrophy

May/June 2017

CASE STUDY

distinct disease or a form of linear scleroderma, although most
authors would agree that these are closely related disorders. The
timing of investigation appears to be a crucial factor in diagnosing either linear scleroderma or PFH, as linear scleroderma lesions have been reported to occur in 3 of 12 patients before the
development of PFH.6 The authors proposed two subtypes of
PFH, one restricted to the subcutaneous tissues and primarily
affecting the cheek area, and one affecting primarily the skin and
only later moving on to the deeper tissues.

hints at an immunologic mechanism involved in the pathogenesis of this condition; however, anti-Scl-70 and anticentromere
antibodies, the most commonly encountered antibodies in
scleroderma, were negative. We are not aware of any previous reports of total hemiatrophy associated with APP. Our observation
could contribute toward a better understanding of the disease.
References

Crossed hemiatrophy shows facial atrophy on one side and atrophy of the periphery and trunk on the other side. It is very rare,
and its cause is not known. In previous reports, Hirata et al described a case of crossed total hemiatrophy with a right precentral
to central arteriovenous malformation.7 The authors suggested
that the ipsilateral facial atrophy might hypothetically be related
to some brainstem dysfunction. Strenge et al reported a 35-yearold man presenting a neurocutaneous disorder with coup de sabre
deformity, telangiectatic naevus, aneurysmatic malformation of
the internal carotid artery, and crossed hemiatrophy.1
The cause and etiopathogenesis of APP remain elusive. Previous
studies suggested that genetic factors, neurogenic causes, immunologic factors, and abnormal metabolism of dermatan sulphate
might play a role in the pathogenesis of APP.8 The role of Borrelia
burgdorferi remains controversial.9 The lesions of APP lesions
may be asymptomatically solitary or multiple patches, which
progress very slowly and remain stable for 10 to 20 years. Most
commonly, they are distributed symmetrically on the trunk.
Some authors regard atrophoderma as a distinct entity, whereas
others suggest that APP is a variant of morphea. Concurrence of
APP and morphea has been reported.10
Conclusions
In our patient, no redness or induration of these lesions was noted. Histopathologically, atrophic dermis and a slightly inflammatory infiltration were observed. Magnetic resonance images
showed slight atrophy of the right cerebral hemisphere. Serologic investigations revealed positive antinuclear antibody, which

A 23-year-old man presented to our practice with erythroderma and an unusual retiform eruption, along with alopecia universalis and nail
dystrophy. He had had no skin findings at birth, but since early infancy had had localized eczematous eruptions of his skin. At 10 years of
age, he had developed a generalized eczematous flare requiring hospitalization, and another generalized episode occurred in October 2010.
He was prescribed prednisone 60 mg daily, which initially provided an improvement, but tapering of the corticosteroid resulted in another
generalized flare. (SKINmed. 2017;15:231–234)

F

or the past 3 to 4 years, the patient had been managed
with prednisone, tacrolimus, and sirolimus, with continued development of eczematous lesions and even ulcerations on his legs. Subsequently, he was switched from sirolimus
to azathioprine; his medications on presentation were prednisone 35 mg daily, tacrolimus 8 mg daily, and azathioprine 50
mg twice daily. The patient’s medical history also included earlyonset type 1 diabetes mellitus diagnosed at 1.5 years of age, inflammatory bowel disease, and growth hormone deficiency.
Physical examination revealed erythroderma with lichenification
of the neck, axillary fold, antecubital fossa, and abdomen. All his
limbs showed yellow, eroded, retiform patches on a background
of livedo reticularis. The patient also had alopecia universalis and
nail dystrophy (Figure 1). Laboratory data revealed an elevated
erythrocyte sedimentation rate of 63 mm per hour (normal 0 to
10 mm per hour), C-reactive protein of 2.0 (normal <0.8 mg/
dl), and elevated levels of interleukin-2R of 3310 IU/ml (normal 200 to 1100 U/ml) and tumor necrosis factor-α 27.7 pg/ml
(normal 1.2 to 15.3 pg/ml). Serum immunoglobulin (Ig) G and
IgE, as well as CD4 and CD8 counts, were within normal limits.

Biopsy of the anterior aspect of the right leg demonstrated a dense
lichenoid lymphohistiocytic infiltrate with numerous necrotic keratinocytes in the basal cell layer, scattered eosinophils, and localized
spongiosis. Periodic acid-Schiff-diastase, Gram, and Steiner stains
were negative (Figure 2). In 2013, the patient underwent genetic
testing in which a portion of the forkhead box P3 (FOXP3) gene
(MIM #300292), which is known to be associated with immune
dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)
syndrome (MIM #304790), was sequenced using the Reference sequence database NM_014009.3. The patient’s DNA was found to
harbor a hemizygous mutation of the FOXP3 gene (c.1150G>A),
confirming a diagnosis of IPEX syndrome. The patient’s mother
and two of his three sisters were also carriers of the FOXP3 gene
mutation.
DISCUSSION
First described in 1982, IPEX is an extremely rare X-linked immune dysregulation disorder characterized by the triad of enteropathy, autoimmune endocrinopathy, and cutaneous manifestations.1 It is caused by a mutation in the gene for FOXP3, an
important DNA-binding protein necessary for the differentia-

From the David Geffen School of Medicine at University of California Los Angeles (UCLA),1 Division of Dermatology, David
Geffen School of Medicine at UCLA,2 Division of Clinical Immunology and Allergy, UCLA,3 and Department of Pathology and
Laboratory Medicine, UCLA,4 Los Angeles, CA
Address for Correspondence: Yen T. Wang, MD, Division of Dermatology, David Geffen School of Medicine at UCLA, 200 UCLA
Medical Plaza, Suite 450, Los Angeles, CA 90095 • E-mail: jywanga@gmail.com

tion and development of CD4+CD25+ regulatory T cells. The
absence of regulatory T cells leads to a loss of self-tolerance and
immune dysregulation.2 Common sequelae include chronic diarrhea, early-onset diabetes mellitus, thyroiditis, dermatitis, susceptibility to infection, hemolytic anemia, and thrombocytopenia. A review of 39 patients with IPEX from 12 separate reports
show that more than 90% of subjects developed enteropathy,
70% developed diabetes, more than 60% developed skin disease,
30% had thyroiditis, and only around 20% developed recurrent
infections. Many IPEX patients do not develop signs of immunodeficiency.3 According to a study by Torgerson and Ochs, only
half of 50 patients had a history of recurrent severe infections.
A disruption of the skin and gastrointestinal mucosal barrier
may be additional contributing factors to the immunodeficiency
state.4 Individuals with similar manifestations but who lack the
FOXP3 gene mutation are said to have “IPEX-like” syndrome,
which accounts for approximately 75% of cases.5 The particular
gene mutation in our patient (c.1150G>A) has been reported
several times in individuals with IPEX syndrome.6
IPEX must be considered in any infant with intractable diarrhea
and type 1 diabetes mellitus. Preliminary studies should include
complete blood count, serum glucose, anti-islet antibodies, thyroid function studies, antithyroid antibodies, antienterocyte antibodies, and immunoglobulin levels. Although autoantibodies
are often detected, a degree of the autoimmune destruction may
be secondary to T-cell–mediated infiltration of the target organs
as well.3 Most patients with IPEX have elevated IgE levels, with
half of those also exhibiting elevated IgA; however, IgG and IgM
levels tend to be normal. On a cellular level, absolute neutrophil
and lymphocyte counts are generally normal, but eosinophilia
may be present.5 CD4+ and CD8+ subsets counts are generally
within normal limits. Proliferation levels in response to mitogen and antigen may be either normal or mildly diminished.
Patients with IPEX exhibit defective interferon-γ, interleukin-2,
and tumor necrosis factor-α production.3 Definitive diagnosis
requires gene sequencing to identify a mutation in the FOXP3
gene.2 Food allergy testing, lymphocyte subsets, proliferation assays and genetic testing should be carried out in consultation
with allergy and immunology departments.
In the literature, 92 of 136 patients (67.6%) reported with IPEX
syndrome have skin manifestations.7 The most commonly described condition is an eczematous dermatitis, correlated with
elevated serum IgE and peripheral blood eosinophil levels. Other
reported cutaneous manifestations include erythroderma, psoriasiform dermatitis, pemphigoid nodularis, exfoliative dermatitis, cheilitis, alopecia universalis, and onychodystrophy.8 To date,
only a few studies have correlated their skin findings with histoSKINmed. 2017;15:231–234

pathology. Most cases have described an eczematoid or psoriasiform pattern, with one case demonstrating histopathologic findings consistent with pemphigoid nodularis.9–11 Our case is the
first documenting a lichenoid dermatitis in a patient with IPEX
syndrome as well as an unusual clinical appearance of eroded,
retiform patches on a background of livedo reticularis.
An autoimmune basis of the skin findings in IPEX syndrome is
plausible given that these patients lack regulatory T-cell function.
One group9 has demonstrated linear immunofluorescence staining of C3 and IgG along the dermal-epidermal junction, and
positivity for the 180 kDa bullous pemphigoid antigen in their
patient with IPEX syndrome and pemphigoid nodularis. Another
patient with IPEX syndrome developed bullous lesions with immunofluorescence showing linear IgG along the roof of the subepidermal separation and C3 deposition along the roof and the
floor, consistent with bullous pemphigoid.12 Antiga et al13 showed
that CD4+CD25+ regulatory T cells were significantly depleted
in the skin lesions and peripheral blood of patients with bullous
pemphigoid. Other studies have found that CD4+CD25+ regulatory T cells are also depleted in skin lesions of atopic dermatitis
and psoriasis.14 The absence of these regulatory T cells may lead
to dysregulation of effector T cells that are responsible for causing
the eczematous or psoriasiform lesions seen in IPEX syndrome.
Usually, untreated IPEX patients die in the first 3 to 4 months
of life from diarrhea and numerous infections, and even with
treatment, the prognosis is poor. Patients are at increased risk for
sepsis, meningitis, pneumonia, and osteomyelitis, with the most
common culprits being enterococcus, Staphylococcus, Cytomegalovirus, and Candida species.4 Long-term management of the
disease requires immunosuppression, which further increases the
risk of infection. Prednisone and corticosteroid-sparing agents
such as tacrolimus, cyclosporine, or sirolimus are commonly
used.15 Management of acute flares may require admission to
intensive care with increased levels of immunosuppression and
isolation to prevent nosocomial infections. Avoidance of possible food allergens may be crucial, and vaccinations are generally avoided to prevent triggering life-threatening disease flares.
Hematopoietic stem cell transplantation is curative, but many
of the endocrinopathies remain because of end-organ damage.15
CONCLUSIONS
We describe a unique case of an adult patient with IPEX syndrome presenting with an unusual appearance of eroded, retiform patches and a lichenoid lymphohistiocytic infiltrate on
histopathology. Further studies are necessary to determine the
pathogenesis of cutaneous manifestations of IPEX syndrome in
relation to CD4+CD25+ regulatory T-cell deficiency.

A 68-year-old woman, with a 75-pack-year smoking history and a history of chronic excess alcohol intake, presented with a 5-week history of worsening perianal pain and ulceration. She recently had an inpatient admission with back pain and urinary tract infection during
which she developed diarrhea and fecal incontinence. Initially, the perianal ulceration was diagnosed as severe irritant contact dermatitis
and treated with barrier creams and topical clobetasone 17-butyrate 0.05% weight for weight, oxytetracycline 3.0% weight for weight and
nystatin cream (Trimovate®). Despite this, the ulceration progressed, resulting in hospital readmission 1 month later. There was no history
of consumption of nicorandil (an antianginal therapy), of recurrent oral ulcers, or of inflammatory bowel disease. On examination, there
were multiple areas of deep, sloughy ulceration bilaterally around the perianal and buttock regions with erythematous and violaceous edges
(Figure 1). Complete blood count, blood film, rheumatoid factor, autoimmune and vasculitic profile, hepatitis screen, immunoglobulins
and plasma protein electrophoresis were all normal. Punch biopsy revealed scanty dermal perivascular inflammatory cell infiltrate and occasional neutrophils (Figure 2). No evidence of granulomata, dysplasia, malignancy, or Langerhans histiocytes was identified, and periodic
acid–Schiff staining was negative. (SKINmed. 2017;15:235–237)

D

uring this admission, the patient also complained of difficulty mobilizing, lower limb numbness, and paresthesia, which, after magnetic resonance imaging of the spine
and a neurology consultation, was felt to be peripheral neuropathy
secondary to nutritional deficiency and previous heavy alcohol
intake. Clinically and histologically, the perianal ulceration was
considered consistent with pyoderma gangrenosum (PG), and she
was treated with intensive dressing regimens, high-dose oral prednisone, minocycline, and subsequently mycophenolate mofetil.
Although the perianal ulceration stabilized with this treatment, no
significant improvement in clinical appearance was noted. Subsequent review revealed bilateral cold dusky feet with bilaterally
absent posterior tibial and dorsalis pedis pulses. An urgent computed tomography angiogram revealed significant stenosis of the
abdominal aorta distal to the renal vessels, occluded common iliac
arteries, and small common femoral arteries with widespread calcified plaques throughout the arterial system (Figure 3).
The patient underwent a successful axillobifemoral bypass graft 5
months after presentation, with improvement in the perianal ulceration. Several months after her surgery, the perianal ulceration

had shown significant resolution, and she was gradually weaned
off treatment for PG. By 15 months after presentation, the prednisone, minocycline, and mycophenolate mofetil had been discontinued, and the perianal ulceration had completely healed.
DISCUSSION
Perianal ulceration can be caused by a myriad of conditions including infections, PG, Crohn’s disease, malignancy and medications; in particular nicorandil, an antianginal therapy used in the
UK, is a common culprit (Table).1–3 PG, a disorder of impaired
neutrophil function, has an incidence of around 3 to 10 per million population, with a female predominance.4,5 It classically
presents as a small papule, rapidly progressing to a deep painful
ulcer with an erythematous, irregular, undermined border and
a necrotic center.6 However, ulcerations may be misdiagnosed
as PG. Weenig et al reviewed 240 patients who had been diagnosed with PG. Of these, 95 patients (40%) had ulcerations
that resembled PG, but later were found to have an alternative
dignosis, for example vascular occlusive/venous disease, vasculitis, neoplasia, primary infection, and drug-induced and other

inflammatory disorders. In addition, for the patients who were
given treatment for PG, around a third showed no improvement, while 13% developed worsening of the ulceration.7 This
SKINmed. 2017;15:235â&#x20AC;&#x201C;237

study highlighted that misdiagnosis can increase both the risks
associated with treatment, and the risks associated with a delay
in diagnosis. Our patient was also initially misdiagnosed as having PG, with treatment leading to only minimal improvement.
However once the patient developed features of vascular insufficiency, appropriate investigations and management were instigated, with subsequent resolution of the ulceration.

236

Ischemia-Induced Perianal Ulceration

May/June 2017

CASE STUDY

We present a challenging case of a patient with ischemia-induced
perianal ulceration, who was initially misdiagnosed as having
PG; however, the ulceration subsequently resolved following
surgical intervention for lower limb ischemia, secondary to stenosis of the abominal aorta and common iliac arteries. Anatomically, the common iliac artery branches into the external and internal iliac artery, with the small branches of the latter supplying
the external genitalia, perineum and buttocks. As such, stenosis
of these vessels will impede blood supply to the aforementioned
anatomical sites, with subsequent cutaneous manifestations as
witnessed in this case.

of considering all potential underlying causes of cutaneous ulceration, particularly in patients with limited or slow response
to treatment.
References

To our knowledge, there are no reported cases of ischemia-induced
perianal ulceration; moreover we could find only one case report
of ischemia-induced PG. In this case, the patient, who had longstanding PG affecting the left lateral malleolus, developed worsening of the ulcerations with subsequent bleeding. Investigation
revealed critical limb ischemia, with surgical intervention (lumbar
sympathetic ganglion block with chemical sympathectomy), significantly improving the ulceration, similar to our case.8
This case highlights that impaired blood flow to the perineum
can cause ulceration, which may mimic PG. While the clinical appearance of the perianal ulceration was initially felt to
be consistent with PG, resolution of the cutaneous ulceration
only occurred following correction of the underlying cause
(vascular surgical intervention) and not with typical therapeutic options for PG alone. This case demonstrates the necessity

Skin and Psyche
Nordlind, K. and Zalewska-Janowska, A, Editors, Skin and
Psyche. Sharjah, UAE, Bentham Books; 2016: 253 pages. ebook only, $39.00
No offense to cave-dwellers, but I’m a troglodyte. A die-hard
paper-and-ink fan, I was apprehensive when first asked to review
this e-book. I have always been intrigued by the psychologic
aspects of skin disease, so my curiosity overruled my technophobia. I was hoping this book would answer questions such
as how stress aggravates so many eruptions and what gives with
delusional parasitosis.
I was wrong. Maybe I should have been forewarned by the title.
I’m pretty sure I know what “skin” means, although after reading the chapter on psychoanalysis, even on that point I’m a bit
disoriented. There is never a specific definition of “psyche”: are we
talking about a tangible set of neurons or an ineffable spirit? The
uneven quality of the individual chapters is annoying. Frequent redundancy suggests that none of the authors read any chapter other
than the one he or she had personally written. Given the numerous misspellings, typographical errors, and (to be charitable) nonstandard English, I sometimes wondered if they read even that.
Enough of generalities. Chapter 2, “Psoriasis and Stress: A Review,” is nothing more than an exercise in cutting and pasting
abstracts from previously published papers. The authors make no
effort to synthesize their disparate collection into a meaningful
whole, nor do they reconcile contradictory findings.
In Chapter 3, “Acne Vulgaris: Psychological State,” there is the
transparently obvious, “We need to remember that the face is the
most conspicuous part of our appearance,” and the totally obscure,
“the biopsychosocial model takes into account factors such as social support and psychological stress as well as factors relating to
physiological disorders or the presence of viruses” (emphasis mine).

Chapter 4, “Body Dysmorphic Disorder—Quick Guide to Diagnosis and Treatment,” contains one of the most obtuse sentences in this oftentimes difficult book: “many patients do not
show habituation to mirroring, possibly explained by the decreased set-shifting capacity and impaired visual and emotional
process resulting in frontostriatal systems unable to inhibit subcortical areas.”
Chapter 5, “Skin Picking Disorders and Dermatitis Artefacta,”
reveals this book’s existential flaw when it states, “where possible,
patients with SPD/Acne excoriee should be managed in a dedicated psychodermatology clinic.” Chapter 10, “Building a Psychodermatology Clinic,” explicitly concedes that such clinics are
practical only within academic centers. Where does that leave a
reader who is in private practice and for whom a psychiatry rotation is just a distant or repressed memory?
Chapter 6, “Understanding the Challenges in Management of
Delusional Infestations,” offers practical treatment options for
these extremely challenging patients.
As alluded to previously, Chapter 9, “Psychoanalysis in Psychodermatological Diseases,” left me feeling unhinged.
Qui bono? Anyone attached to a psychodermatology clinic will
probably find this book unnecessary. Conversely, a typical dermatologic practice would be hard pressed to find the time for
(or, quite frankly, absorb the unreimbursed costs of ) most of this
book’s recommendations. The authors rightfully emphasize how
crucial it is to be sensitive to the emotional, dare I say “psychic,”
burdens of skin diseases. There is recognition that not only can
psychologic factors affect the skin, but skin conditions can also
have a profound impact on one’s sense of self and well-being.
This far-from-perfect book provides a useful reminder that we
treat people not skin eruptions.

Molecular Mechanisms of Skin Aging
and Age-Related Diseases
Quan T., ed. Molecular Mechanisms of Skin Aging and AgeRelated Diseases. Boca Raton, FL, CRC Press, Taylor & Francis Group, 2016: 263 pp, $169.96 hardcover, $139.97 e-book
“Youth is wasted on the young.”
This quote, probably based on the words of George Bernard
Shaw, reminds us that youth is fleeting and gone before we grasp
its significance. Then we age and become older. Can the aging
process be slowed down? So far, there is no magical fountain
of youth that can reverse all the effects of time and restore our
childhood look and youthful vigor. Medicine, however, is making progress with a better understanding of the complexities of
the human aging process. This knowledge may help us to find
better ways to improve human longevity and the quality of life
during later years.
Molecular Mechanisms of Skin Aging and Age-Related Diseases provides a superb review of recent progress in understanding the
molecular mechanism of human skin aging. The book consists
of 12 chapters written by 27 authors from all over the world. The
information provided is comprehensive but easy to follow with
the accompanying figures and chapter conclusions.
The study of skin aging is important, because skin appearance
helps define whether one looks young or old. In addition, as
noted in a fascinating chapter entitled “Aging Skin: A Window
to the Body,” the skin can be considered a “keyhole” in observing the aging process of the whole organism. Clinically, aged
skin is recognized by the appearance of wrinkles, sagging, age
spots, and dryness, with many of the chapters elaborating on the
pathology and molecular features of aging skin. I was awed by
those chapters.
Aging skin, on a microscopic and molecular level, looks like a
nuclear wasteland. There is collagen fragmentation and impaired
dermal fibroblast function, accompanied by epidermal barrier

impairment and skin dryness. There is also mitochondrial DNA
common deletion that occurs in the aging of human skin connective tissue. All of this just begins to scratch the surface of
what goes wrong during the skin aging process on a molecular
level. With all these molecular abnormalities going on, can we
really hope to stop the aging process? The answer, I think, will
not come through some magical revelation; rather, progress in
the fight against aging will occur in smaller steps by using basic
research to develop rational therapies that better treat and prevent age-related skin problems.
The book briefly mentions Hutchinson-Gilford progeria, a rare
genetic disease with clinical features of premature aging. Impressive progress has already been made in unraveling the genetic
defect in progeria and in instituting beneficial therapy for children suffering from this disorder. Readers may be interested to
learn about a new condition, not discussed in the book, known
as “syndrome X,”1 where children remain physically and cognitively similar to an infant or toddler despite increasing age. The
amazing contrast between progeria, in which the aging process
dramatically speeds up, and syndrome X, in which children seem
to remain ageless, is most striking. These two seemingly opposite
clinical disorders suggest that there exists a certain “relativity” to
the human aging process that could, one day, be manipulated to
slow down human aging and forestall its deleterious effects upon
the body.
This book provides a nice overview of what is meant by the terms
“intrinsic aging” and “extrinsic aging,” as well as a useful summary of skin conditions found in elderly patients and their clinical management.
Reference
1 Walker RF, Liu JS, Peters BA, et al. Epigenetic analysis of children who seem to be evading aging. Aging.
2015;7:334–339.